Basis for skin notation. Part 1.

nr 2008;42:2

Basis for skin notation. Part 1. Dermal penetration data for substances on the Swedish OEL list Gunnar Johanson, Matias Rauma

arbete och hälsa

|

isbn 978-91-85971-02-2

vetenskaplig skriftserie issn 0346-7821

Arbete och Hälsa Arbete och Hälsa (Work and Health) is a scientific report series published by Occupational and Environmental Medicine, Sahlgrenska Academy, Göteborg University. The series publishes scientific original work, review articles, criteria documents and dissertations. All articles are peer-reviewed. Arbete och Hälsa has a broad target group and welcomes articles in different areas. Instructions and templates for manuscript editing are available at http://www.amm/se/aoh Summaries in Swedish and English as well as the complete originial text as from 1997 are also available online.

Arbete och Hälsa Editor-in-chief: Kjell Torén Co-editors: Maria Albin, Ewa Wigaeus Tornqvist, Marianne Törner, Wijnand Eduard, Lotta Dellve and Roger Persson Managing editor: Gunilla Rydén Editorial assistant: Anna-Lena Dahlgren © Göteborg University & authors 2008 Arbete och Hälsa, Göteborg University, S-405 30 Göteborg, Sweden ISBN 978-91-85971-02-2 ISSN 0346–7821 http://www.amm.se/aoh Printed at Elanders Gotab, Stockholm

Editorial Board: Tor Aasen, Bergen Berit Bakke, Oslo Lars Barregård, Göteborg Jens Peter Bonde, Århus Jörgen Eklund, Linköping Mats Eklöf, Göteborg Mats Hagberg, Göteborg Kari Heldal, Oslo Kristina Jakobsson, Lund Malin Josephson, Uppsala Bengt Järvholm, Umeå Anette Kærgaard, Herning Ann Kryger, Köpenhamn Svend Erik Mathiassen, Gävle Sigurd Mikkelsen, Glostrup Gunnar D. Nielsen, Köpenhamn Catarina Nordander, Lund Karin Ringsberg, Göteborg Torben Sigsgaard, Århus Staffan Skerfving, Lund Kristin Svendsen, Trondheim Gerd Sällsten, Göteborg Allan Toomingas, Stockholm Ewa Wikström, Göteborg Eva Vingård, Uppsala

Preface Skin notations are used by many organizations and in many countries including Sweden. Thus, substances that may easily be absorbed percutaneously are marked with an “H” in the Swedish provisions on occupational exposure limits (OELs) (AFS 2005). This procedure started already with the first list of OELs introduced in 1974. OELs are given for 368 substances or substance groups in the present provisions (AFS 2005). Out of these, 101 substances/groups (27%) have a skin notation. No formal or quantitative criteria have been developed in Sweden. The intent was originally that the skin notation would give a qualitative indication of possible dermal absorption of the chemical at work. In other words, the attempt was mainly to evaluate the ability of penetration through intact “healthy” skin, i.e. the intrinsic properties of the chemical relative to skin. In an international perspective the criteria for assigning a skin notation vary widely but are generally qualitative rather than quantitative in nature. During the last few years, however, focus has shifted towards more quantitative assessments, either by expressing the intrinsic properties of the chemical in numerical terms, such as dermal absorption rate (flux) at defined conditions or by expressing the systemic exposure (absorbed dose), i.e. a combination of the intrinsic properties and the exposure conditions (exposed skin area, exposure duration etc). In view of the large and increasing numbers of H-labeled substances, there is a need for more formal criteria. There is also a risk that the warning effect of the label is diminished if too many substances are labeled. In view of these concerns, the Swedish Work Environment Authority (SWEA) has initiated a project with the aim to develop new criteria and procedures for skin notation. As input for the project, SWEA requested the Division of Work Environment Toxicology at the Institute for Environmental Medicine, Karolinska Institutet to produce two reports on dermal absorption in relation to skin notations and OELs. The aim of the first report, presented herein, is to describe methods used to measure dermal absorption and to compile and evaluate published quantitative data on dermal absorption focusing on substances listed in the ordinance on Swedish OELs (AFS 2005). The second report will address different approaches to skin notation. Literature searches, compilations and writing of the report were carried out by MSc Matias Rauma and professor Gunnar Johanson at the Division of Work Environment Toxicology. The final literature search was performed in January 2007. The cited papers were to a large extent supplied by the library at the Swedish National Institute for Working Life.

The major sources used were: -

Medline,

-

the EDETOX database on the web (www.ncl.ac.uk/edetox/),

-

consensus reports and criteria documents (and publications cited therein) published by the Swedish Criteria Group for Occupational Standards at the National Institute for Working Life,

-

criteria documents (and publications cited therein) published by the Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals (NEG),

-

the documentation (and publications cited therein) published by the Chemical Substance - Threshold Limit Values (CS-TLV) Committee of the American Conference of Industrial Governmental Hygienists (ACGIH), and

-

secondary sources, i.e. references given in the above sources.

We wish to express our gratitude to associate professor Anders Boman (Occupational and Environmental Dermatology, Karolinska Institutet, Stockholm), professor Magnus Lindberg (Dermatology Unit, Örebro University Hospital), associate professor Pierre-Olivier Droz (Institute of Occupational Health, Lausanne), Dr. Karin Sørig Hougaard (National Research Centre for the Working Environment, Copenhagen) and associate professor Margareta Warholm (SWEA, Solna) for valuable comments on the manuscript. We are also grateful to MSc Tina Isaksson for compilation of some of the data. The investigation was financially supported by the Swedish Work Environment Authority.

Stockholm July 2007

Gunnar Johanson

Matias Rauma

Contents 1. Introduction 2. Anatomy of the skin 3. Skin as a diffusion barrier 4. Fick’s law of diffusion 5. Factors affecting dermal penetration Concentration Properties of the chemical Properties of the skin Summary 6. Assessment of dermal penetration In vivo tests In vitro tests Structure-activity based methods 7. Dermal penetration data for substances on the Swedish OEL list Approach Conclusions 8. Summary 9. References

1 2 4 6 7 7 8 8 11 12 12 13 15 17 17 19 31 32

Appendices A. Tabular data for individual substances B. References to individual substances Octanol:water partition coefficients Other physical properties Scientific bases Other physical properties

A1-A181 B1 B1-B2 B2 B3 - B16

1. Introduction The aim of this report is to review the published data on dermal penetration of workplace chemicals, as a basis for assignment of skin notations. Dermal exposure is a major route of systemic exposure at work. Along with reductions in OELs and occupational exposure via air, the dermal route has become even more important. Data on dermal absorption are input for so called skin notations. Skin notations are used as warning signals for chemicals that may easily be taken up via the skin, thereby causing - or increasing the risk of - systemic toxicity (see e.g. AFS 2005, SCOEL 1999). The decision to assign a skin notation is largely based on the ability of the chemical to penetrate skin. Sometimes experience from work practice is also considered, so that chemicals for which health effects have been seen at work after (presumed) dermal exposure are also assigned with a skin notation. Direct effects on the skin, such as irritation, corrosion and sensitization, are usually not considered. The criteria for skin notations and their practical application are beyond the scope of the present report but will be described and discussed in a second report. Nevertheless, it should be mentioned that the relations between the presence of a chemical in the work environment and dermal dose, as well as that between dermal dose and systemic dose is very complex and highly variable. Thus, the first relationship is affected by a number of factors, such as the volatility and other properties of the chemical, how the chemical is used, the work process, the individual’s behavior and work practices, type of clothing and protective equipment, and so on. The influence of some of these factors may be highly variable and is often difficult to predict. The second relationship (and the focus of this report) depends on the properties of the chemical and the skin and is, at least in principle, more easily described and measured.

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2. Anatomy of the skin The skin provides a barrier between the human body and its environment. The major function is to prevent loss of water and heat to the environment. It also protects the body from mechanical, biological and chemical hazards. The skin is the largest organ of the human body (15% of total adult body weight). The skin consists of three layers (from inside to outside): hypodermis, dermis, epidermis (figure 1). The hypodermis (subcutis) is the deepest part of the skin and contains mainly adipose tissue. The subcutaneous layer is important for protection from mechanical injuries, energy provision, thermoregulation and insulation. Hair Sebaceous gland

Epidermis Nerve Muscle Dermis Sweat gland

Capillaries

Hypodermis

Arteriole

Venule

Figure 1. Drawing of the skin (adapted from http://www.nku.edu/~dempseyd/SKIN.htm).

The dermis contains connective tissue and provides elasticity, flexibility, strength and stability to the skin. The main cells are fibroblasts (synthesizing the collagen fibres), dermal dendrocytes and mast cells (belonging to the immune system). The dermis is in close contact with the abundant ridges and grooves of the epidermis. The ridges are enlarging the surface area between dermis and epidermis, allowing for a better adhesion and a more efficient exchange of nutrients and waste. Both the dermis and hypodermis are richly innervated and vascularized. The skin appendages (hair, nails, sweat glands, sebaceous glands) originate in these parts of the skin, mostly in the dermis. The epidermal layer consists mainly of keratinocytes (90-95%), Langerhan’s cells (skin immune response), melanocytes (skin color and UV protection) and Merkel cells (slow-adapting mechanoreceptors for touch). The keratinocytes are constantly being replaced. The shape of the cells changes during their migration from the innermost part of the epidermis towards the surface of the skin (figure 2).

2

Based on the appearance in the microscope, the epidermis is subdivided in five different layers (from inside to outside): stratum basale, stratum spinosum, stratum granulosum, stratum lucidum and stratum corneum (figure 3). Stratum corneum, with dead keratinized cells at surface

Cells flatten as they migrate toward the surface

Stratum basale with dividing stem cells

Figure 2. The maintenance of the epidermis (adapted from http://www.mhhe.com/biosci/ap /histology_mh/stratepi.html).

The stratum corneum consists of several layers of completely keratinized dead cells without a nucleus (corneocytes). The cells are stacked, leaving little space between them. Keratin is a tough, insoluble protein that is also the chief structural constituent of hair, nails, and hooves. Thus, the stratum corneum mainly consists of keratin and highly resistant to diffusion of water and other molecules (figure 3). Thick skin has many layers of corneocytes cemented together. Thin skin has fewer layers of living and dead cells but the same overall structure.

Stratum corneum, 10-30 cell layers Stratum lucidum, 1 cell layer Stratum granulosum, 2-3 cell layers

Stratum spinosum, 2-7 cell layers

Stratum basale, 1-2 cell layers Basal membrane Dermis

Figure 3. The five layers of the epidermis (adapted from Forslind & Lindberg 2004).

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3. Skin as a diffusion barrier A major function of the skin is to prevent loss of water to the environment. The humidity in the ambient air is often low and without an effective barrier the organism would rapidly loose large amounts of water. This would preclude life on land. The major diffusion barrier is the stratum corneum. However, this skin layer is not entirely impermeable. Water as well as other small molecules diffuse more or less slowly through the skin. Water is very important to maintain the flexibility of the skin. Dry skin becomes rough and flaky and completely dried stratum corneum is reduced to a very brittle, thin sheet. Water is also important for thermoregulation, as the heat used to evaporate the water excreted via sweat glands lowers the temperature of the skin. In principle, there are three possible diffusion pathways through the skin. The major route, especially for fat soluble, nonpolar molecules, is likely to be the intercellular lipid pathway. Due to the brick and mortar structure (figure 4), the “true” diffusion path is very much longer than the thickness of the stratum corneum. The diffusional pathlength has been estimated to be as long as 500 µm for stratum corneum of 20 µm thickness (Hadgraft 2004). Further, since impermeable corneocytes make up most of the skin and intercellular lipids constitute only a small part, the area accessible for diffusion is very small compared to the total skin area. Another factor that complicates diffusion is that the intercellular spaces contain structured lipids and a diffusing molecule has to cross a variety of lipophilic and hydrophilic domains.

Diffusion pathway

Corneocytes

Intercellular lipids

Figure 4. Brick and mortar structure of the stratum corneum showing dense, keratinized corneocytes, intercellular lipid layers and one of the diffusion pathways.

4

The second possibility is that of transcellular permeation, i.e. that the molecules diffuse through the corneocytes. A third route of absorption is through the appendages (hair follicles). In most cases, this route is insignificant as the area of appendages is very small compared to the total skin area. However, in the initial phase of the absorption and for very slowly permeating chemicals, this route may be of importance. The structure of the skin and the stratum corneum contrasts that of the lungs and the respiratory airways. Thus, whereas the skin is designed to resist diffusion (and loss of water) the lungs are built to facilitate diffusion (uptake of oxygen and release of carbon dioxide). In the skin, this is manifested by: -

a relatively small surface area (approximately 2 m2 in a human adult), and

-

a stratum corneum consisting of several densely packed layers of cells filled with highly resistant protein (keratin), resulting in high resistance long diffusion pathways (figures 2-4).

In contrast, the alveolae in the lungs have: -

a relatively large surface area (approximately 80 m2 in a human adult), and

-

only two thin cell layers (alveolar epithelium and capillary endothelium), resulting in a low resistance, short diffusion distance from ambient air to blood (figure 5).

Figure 5. Transmission electron micrograph of the lung showing as: the alveolar airspace and c: the capillary lumen, separated by two thin cell layers with a total thickness of about 1 µm (taken from http://www.cf.ac.uk/phrmy/PCB/PageLungAlveolarepithelium.htm).

5

4. Fick’s law of diffusion The driving force for dermal absorption of practically all chemicals is diffusion, i.e. the spontaneous movement of molecules. The flux of molecules from the outer side to the inner side of a barrier (for example the skin) is proportional to the number of molecules at the outer side and the resistance of the barrier. Likewise, the flux from the inner to the outer side is proportional to the number of molecules at the inner side and the resistance of the barrier. The net flux is the difference between the two fluxes and can be described mathematically as: P = Kp x ( A1 – A2 ) Equation 1 is known as Fick’s first law of diffusion. The parameter P is the net flux (number of molecules per time unit) and Kp is the permeability coefficient (resistance to diffusion). A1 and A2 the number of freely moving molecules outside and inside the barrier, respectively. Chemical activity is a measure of how different molecules in a non-ideal gas or solution interact with each other. For very dilute gases and solutions, molecular interactions are negligible and activity is also proportional to concentration. For gases, activity is proportional to partial pressure. A can thus be substituted by thermodynamic activity, partial pressure or, for dilute solutions, concentration. Such substitution will only alter the value of Kp, as these parameters are directly proportional to the number of molecules. In most cases with dermal exposure to chemicals, the concentration at the inner side (in the body) is negligible compared to the outer side (skin surface) and may be approximated to zero. In this case, the flux depends only on the Kp and the concentration at the outer skin surface. Obviously, the value of, Kp depends on the properties of both the skin and the chemical. Further, the numerical value and units of Kp depend on the units chosen for P and A. It is common to express Kp in cm/h, from which follows that suitable units for P are µmol/h/cm2 or mg/h/cm2. A is then expressed as µmol/cm3 (mM) or mg/cm3.

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5. Factors affecting dermal penetration In this report the term dermal penetration is used for the amount of chemical that passes through the skin and reaches the systemic circulation. A synonymous term is percutaneous absorption. These two terms are different from dermal absorption which denotes the amount of chemical that has entered the skin from the outer environment. The dermally absorbed chemical may stay in the skin, diffuse back to the outer environment, be metabolized or pass on to the inner environment (penetration). If excess chemical is applied on the skin for a sufficiently long time (so that a steady-state is reached) and if metabolism in the skin is negligible, penetration equals absorption. From equation 1 in Chapter 4 follows that the unit penetration rate (flux) across the skin is directly proportional to: -

the concentration (activity, partial pressure) of the chemical at the skin surface (provided that the inner concentration is negligible) of the chemical, and

-

the permeability of the skin (expressed by Kp).

The permeability depends on the properties of the chemical as well as the properties of the skin. The total penetration is proportional to (in addition to concentration and permeability): -

the exposed area (since Kp is expressed per area unit), and

-

the duration of exposure.

5.1 Concentration Other factors held constant, the flux is always proportional to chemical activity (figure 6, left), the slope is determined by the permeability coefficient (Kp). At high concentrations, e.g. when the skin is exposed to neat chemical, the molecules begin to interact so that the concentration is no longer proportional to the number of freely moving “particles”. Hence, the relation between flux and concentration becomes sublinear at high concentrations (figure 6, right). In conclusion, dermal absorption rates cannot easily be translated from one concentration to the other and experimentally determined values for Kp are concentration-dependent.

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Dermal abs. rate

Dermal abs. rate Activity gradient (A1-A2)

Conc. gradient

Figure 6. According to Fick’s first law of diffusion (see also Chapter 4), the dermal absorption rate is proportional to the activity gradient (A1-A2) over the skin. The rate is further proportional to the concentration gradient for diluted, but not concentrated, chemicals.

5.2 Properties of the chemical Molecular size and solubility are the major physical properties that determine the diffusion coefficient. Small molecules diffuse more easily through the skin than big molecules. Further, substances such as many organic solvents that easily dissolve in nonpolar (lipids) as well as polar (water) media, diffuse more easily through the skin. Conversely, substances that are either ionized, highly lipophobic or highly hydrophobic exhibit low skin permeability. 5.3 Properties of the skin A thicker keratin layer of the stratum corneum will make the diffusion path length longer and, hence, the permeability lower (=higher resistance). Roughly, the Kp is inversely proportional to the thickness of the stratum corneum. The number of cell layers as well as the thickness varies widely between different parts of the body. At the extreme ends are the genitals with as little as 6 and the heels with as much as 86 cell layers (table 1).

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Table 1. Number of stratum corneum cell layers at different locations (from Ya-Xian, Suetake et al. 1999). Location

Number of cell layers (mean±sd)

Genital Ear Eyelid Face Lip Scalp Trunk Extremities Dorsum of hand Dorsum of foot Palm Sole Heel

6±2 7±2 8±2 9±2 10 12±2 13±4 15±4 25±11 30±6 50±10 55±14 86±36

The palms and soles, and especially the heels, have the thickest stratum corneum of as much as 1.5 mm, whereas that of the eyelids is as little as 0.05 mm. Densely furred species such as rats and mice have a much thinner skin than hairless species, such as humans and pigs. This difference includes the stratum corneum, as well as the epidermis (figure 7).

5

4

Thickness (µm)

50 40

3

30 2 20 1

Stratum corneum thickness Epidermal thickness Epidermal cell layers

Rat

Rabbit

Pig

0 Mouse

Human

Horse

Dog

Cow

Cat

0

Monkey

10

No. of epidermal cell layers

60

Figure 7. Thickness of stratum corneum and epidermis. The figure is based on measurements of the skin over the shoulder (animal data from Monteiro-Riviere, Bristol et al. 1990, human data from Sandby-Möller, Poulsen et al. 2003).

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The stratum corneum is optimized to provide minimum permeability (maximum resistance) at “normal” conditions. Various conditions and factors may affect the structure of the stratum corneum, thereby increasing permeability. These conditions include skin damage caused, e.g. by disease, detergents or ultraviolet radiation, as well as temperature and humidity. There is little data on the influence of skin lesions on dermal penetration in exposed human populations. A recent case report on four workers with different skin status (healthy, erythematous and burned skin and dishydrotic eczema) envolved in exposed to ortho-toluidine during rubber vulcanisation suggests that the absorption of o-toluidine is 1.5- to 2-fold higher through damaged than through healthy skin (Korinth, Weiss et al. 2006). In a follow-up study with 51 workers occupationally exposed to aniline and o-toluidine, the hemoglobinaromatic amine-adduct levels in workers with erythema were on average 73% higher than in workers with healthy skin (Korinth, Weiss et al. 2007). Similar results have been obtained in animal experiments. The permeation of hydrocortisone was studied in vitro using skin from a monkey diagnosed as having eczematous dermatitis. The permeation was approximately twice as high in eczematous skin, as compared to unaffected skin from the same individual. The absorption of another anti-inflammatory steroid, triamcinolone acetonide, was also enhanced through the eczematous skin (Bronaugh, Weingarten et al. 1986). Soap washing and dermal exposure to solvents causes extraction of stratum corneum lipids, and increased permeability. Thus, for example, experimental 3-h treatment of human skin in vitro with 0.1% or 0.3% sodium lauryl sulphate caused an impaired barrier function as indicated by up to three-fold increases in the penetration of tritiated water and various pesticides (Nielsen 2005). In hairless mice topically treated with acetone, the permeation of hydrophilic substances (sucrose, caffeine, hydrocortisone) increased through stratum corneum as well as whole skin in vitro. In contrast, the permeation of lipophilic substances (propegesterone, estradiol) increased through stratum corneum but not whole skin (Tsai, Sheu et al. 2001). Considering ultraviolet radiation, the permeation methanol and ethanol nearly tripled through UVA-treated as compared to untreated human human epidermis. In contrast, the permeation of higher, more lipophilic primary alcohols (propanol, butanol, hexanol, and heptanol) was not significantly altered (McAuliffe & Blank 1991). Increased skin temperature increases the kinetic energy, .i.e. the movements, of the molecules, thereby affecting the lipid structure in the stratum corneum. Also, skin humidity increases as a result of sweating. All these factors may increase the dermal penetration. Johanson and Boman (1991) demonstrated that the percutaneous absorption of 2-butoxyethanol vapour was slightly increased at 33ºC ambient air temperature and 71% relative humidity, as compared to 23ºC and 29% relative humidity. In vitro experiments with freshly prepared human skin showed that the permeability coefficient of benzene in water nearly doubled at 50ºC and decreased slightly at 15ºC, as compared to 26ºC (Nakai, Chu et al. 1997).

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5.4 Summary The permeability of a given piece of skin for a specific substance is reflected by the permeability coefficient. The permeability coefficient is mainly determined by the: -

properties of the chemical,

-

properties of the vehicles (if present),

-

thickness of the keratin layer in stratum corneum,

-

condition of the skin, e.g. skin damage.

The thickness of stratum corneum varies widely between species and between different parts of the body. The condition of the skin varies with, e.g. the temperature and the degree of hydration of the skin.

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6. Assessment of dermal penetration In principle, studies of dermal absorption measures the diffusion of the test substance from a test preparation placed on the skin through the stratum corneum and into the skin. The methods can be divided into two categories: in vivo and in vitro. 6.1 In vivo tests The rat is the most commonly used species for in vivo testing. However, a wide variety of other species and strains are being used, including (hairless) rats, humans, monkeys, dogs, pigs, mini pigs, (hairless) guinea pigs, and (hairless) mice. In vivo studies in laboratory animals are preferably conducted as described by OECD (2004). In brief, the exposed area, ideally about 10 cm2 in rats, should be defined by a device that is attached to the skin surface. The test sample is applied to the surface of skin and allowed to remain for a specified period of time, relevant to human exposure. At the end of the exposure period excess sample is removed. During the study, animals are housed individually in metabolism cages from which excreta are collected. If measurable volatile metabolites (such as radiolabelled carbon dioxide) are expected, exhaled breath is also collected. At the end of the study, the removable remains of the dose are washed from the skin surface. The animals are then killed and the amount of parent chemical and metabolites in skin, carcass and excreta is determined. These data allow for an estimate of the total recovery of the test substance. Test chemical remaining in the skin after wash-off will disappear over time by four pathways, by diffusion into the environment, by desquamation (shedding of the outer layers of the skin), by ingestion when the animal grooms itself, and by diffusion into the systemic circulation. To avoid overestimation of the systemically absorbed dose, measures have to be taken to prevent grooming of the site of application, and to prevent desquamated skin from falling into the urine and fecal collection systems. The skin absorption of the test substance can be expressed as the percentage of dose absorbed per unit time or, preferably, as an average absorption rate per unit area of skin, e.g. μg/cm2/h. By necessity, in vivo studies in humans must use a different experimental protocol, as the total recovery cannot be directly determined. The dermal dose is thus determined indirectly, by comparison to a known dose, for instance the net uptake by inhalation exposure (Dinhaled), where the bioavailability is known to be 100%. The dermal uptake, or rather, the systemic dose via the dermal route (Ddermal), may then be calculated for example by comparing the urinary recoveries of the chemical or its metabolite(s) (R). Alternatively, since the area under of the

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concentration-time curve (AUC) in e.g. plasma or blood is proportional to dose, dermal uptake may be obtained by comparing the two AUCs. Thus: Ddermal Dinhaled = Rdermal Rinhaled

⇒

Ddermal =

Dinhaled ⋅ Rdermal Rinhaled

(2)

or Ddermal Dinhaled = AUC dermal AUC inhaled

⇒

Ddermal =

Dinhaled ⋅ AUC dermal AUC inhaled

For examples of this approach, see e.g. studies by Johanson and colleagues (Johanson & Boman 1991, Johanson, Boman et al. 1988, Johanson & Fernström 1986, 1988). A different approach to measure dermal absorption is that of microdialysis. A small probe equipped with a semi permeable hollow fiber is inserted superficially into the dermis, parallel to the skin surface. A physiological solution is slowly pumped through the fiber, allowing the solutes of interest to equilibrate with the surrounding extracellular space. For overviews, see e.g. Anderson (2006), Schnetz & Fartasch (2001) or Stahl, Bouwet et al. (2002). Human pharmacokinetic microdialysis has only been carried out for two decades and there is limited data, mainly on pharmaceutical drugs, on dermal absorption using this technique. There are several difficulties in obtaining quantitative measures, maybe the major one being that concentration and not flux is measured. The concentration will depend not only on influx via stratum corneum but also on outflux via the blood stream. Other related difficulties reside in determining the position of the probe (since the concentration decreases with distance from the skin surface) and in defining the exposed skin area. 6.2 In vitro tests Skin from many mammalian species, including humans, as well as nonmammalian species, e.g. snakes, can be used. The receptor compartment of a socalled static diffusion cell or Franz cell (figure 8) is filled with a suitable fluid. An excised skin sample is mounted on top of the cell so that the inner side is in close contact with the receptor medium. The test sample is applied in the donor compartment so that it covers the skin surface. For more detailed descriptions, see e.g. the OECD guideline (2004).

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Donor compartment containing chemical or preparation to be studied Skin piece is mounted here Sampling site Receptor compartment containing buffered saline or other suitable medium Heated water compartment, connected to a thermostatted water bath Magnetic stirrer.

Figure 8. Static diffusion cell for dermal absorption studies in vitro.

As in the in vivo studies, the exposure duration should be relevant for human situations. At the end of exposure, excess sample is removed from the skin by appropriate cleansing. The receptor fluid is sampled at defined time points throughout the experiment and the concentration of the parent chemical as well as any significant metabolite(s) is determined by a suitable method, e.g. gas chromatography, to ascertain the mass of the test substance (including any significant metabolite) that has passed through the skin. At the end of the study, the dislodgeable dose, the amount contained in the skin and the amount in the receptor fluid are determined. These data are necessary to calculate the total skin absorption, and allow for an estimate of the total recovery of the test substance. When calculating the dermal penetration rate, the concentration in the receptor fluid translated to absolute mass by multiplying with the volume. The absolute mass rate, i.e. the increase in mass with time during steady-state condition, is obtained as the slope of the linear part of the mass versus time curve (figure 9). Finally, the unit penetration rate or flux is obtained by dividing the mass rate by the exposed skin area.

14

C

25

Mass

20

B

15 10

A 5 0 0

10

20

30

Time

Figure 9. Mass of chemical versus time in the receptor medium static diffusion cell. A: Lag time of skin penetration, B: Steady-state, slope of increase equals penetration rate, C: Penetration rate decreases (curve levels off), either due to back diffusion (limited solubility in receptor medium) or depletion at donor site.

It has to be assured that the test chemical is sufficiently soluble in the receptor medium. For highly water soluble chemicals this is no problem and physiological saline or isotonic buffer are sufficient as solvents. However, if this kind of receptor medium is used with non-polar, poorly soluble chemicals such as hexane, an equilibrium will soon be established between the donor and the receptor compartment (phase C in figure 9). Thus, the net movement of chemical approaches zero and the flux and permeability coefficient may be seriously underestimated. The static diffusion cells may be replaced by a flow-through, so-called Bronaugh cell. Advantages of the latter type of cell are that saturation of the receptor medium can be avoided and that the system can easily be automated by connecting to an autosampler. 6.3 Structure-activity based methods Several regression equations have been developed that relates permeability coefficients to easily obtained chemical properties, such as the octanol:water partition coefficient (Kow) and molecular weight (MW). The Kow is thought to represent the solubility and MW the size and hence diffusivity of the molecule in the skin. The equations are often of the form (McCarley & Bunge 2001):

log K p = a + b ⋅ log K ow + c ⋅ MW

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The constants a, b, and c are determined by fitting the equation to specific experimental data sets. One of the most commonly referred equations was developed by Potts and Guy (1992):

log K p = −2.72 + 0.71 ⋅ log K ow − 0.0061⋅ MW where Kp is expressed in cm/h. More complicated models have also been developed, e.g. the modified Guy (Wilschut, ten Berge et al. 1995), the Cleek and Bunge (1993), the McKone and Howd (1992), the modified Robinson (Wilschut, ten Berge, Robinson & McKone 1995) and the Frasch model (2002). The US National Institute of Occupational Safety and Health (NIOSH) has developed an on-line skin permeation calculator that makes use of the Potts and Guy, the modified Robinson and the Frasch models (figure 10). These equations generally work well within homologous series and structurally related chemicals, but are often unreliable outside that range. The error may be up to one or two orders of magnitude, compared to experimental data.

Figure 10. Screen dump of the US NIOSH skin permeation calculator available at http://www.cdc.gov/niosh/topics/skin/skinPermCalc.html.

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(5)

7. Dermal penetration data for substances on the Swedish OEL list 7.1 Approach

Published percutaneous absorption data were searched for 165 substances. The compilation includes all 117 substances denoted with “H”, i.e. a skin notation in the ordinance on Swedish OELs (AFS 2005). In addition, 50 listed substances without skin notation but with published quantitative data on dermal absorption were included. Detailed information on each substance is given in the Appendix. All substances in the Appendix except nicotine correspond to a defined entry with its own value in the Swedish ordinance. For nicotine the indicative OEL value of the European Commission should be used as a recommendation pending the introduction of a Swedish OEL. A few closely related substances, e.g. the PCB congeners, the mercury salts and the dinitrotoluene, butyl amine and cresol isomers, are given a single OEL in the Swedish list. Thus, the 165 substances correspond to 150 OEL entries. All published dermal uptake data were listed for each substance. The compilations include information on species, type of experiment (in vitro/in vivo), type of diffusion cell, skin location, thickness and area, vehicle, concentration, number of experiments, exposure duration, observation time, lag time of penetration and percent absorbed chemical. Abbreviations and terms are given in table 2. Flux and permeability (Kp) are either listed as stated by the authors or calculated by us (numbers in italic). In addition, physico-chemical properties are provided for each substance. This includes molecular weight, density at 25ºC, melting and boiling points, vapor pressure at 25ºC and evaporation rate relative to n-butyl acetate. These properties were obtained from Chemfinder (http://chemfinder.cambridgesoft.com), Swedish consensus reports published in Arbete och Hälsa, the NIOSH Pocket Guide to Chemical Hazards, and data on the internet supplied by various companies and organizations (see Appendix for references). Octanol:water partition coefficients were obtained using the KowWin software from Syracuse Research Corporation (http://www.syrres.com/esc/kowwin.htm). In cases with multiple data, a preferred data set (marked by dots in figure 12) was selected according to the following criteria: 1. Human skin preferred over animal skin 2. In vivo studies preferred over in vitro studies 3. Neat liquid preferred over vapor or diluted liquid 4. Water preferred over other vehicles 5. Infinite or large dose preferred over low dose

17

Infinite or large doses, although perhaps unrealistic considering workplace conditions, were preferred over low doses as they allow for assessment of steadystate fluxes. Although experimental exposure to neat (pure) chemical may affect the skin barrier and may reflect reality less well than exposures to vapors and dilutions, the former type of studies was preferred for two reasons; (a) they are more common facilitating comparisons between and ranking of chemicals and (b) they are less dependent on exposure conditions and thus more closely reflect the intrinsic properties of the chemical. The motives for selecting the preferred study for each individual chemical are given in the Assessment section of each substance in Appendix A. Based on the preferred Kp value, substances were grouped in seven categories, from “Extremely low” to “Extremely high” permeability, according to a logarithmic scheme (figure 11) slightly modified from Marzulli et al. (1965) and Barber et al. (1995). 10

0

10

-1

10

-2

10

-3

Extremely high Very high

Kp, cm/h

High Moderate 10

-4

10

-5

10

-6

Low Very low Extremely low 10

-7

Figure 11. Grouping scheme according to skin permeability (Kp). The grouping does not take toxic potency into account.

For chemicals lacking quantitative data, indirect data such as comparisons between oral and dermal LD50 values and other statements on dermal penetration ability were identified in the documentation published by the Swedish Criteria Group and by the Threshold Limit Value Committee of the American Conference for Governmental Industrial Hygienists. These statements, if any, are also provided in the Assessment section.

18

7.2 Conclusions

Quantitative dermal penetration data were missing for 53 of the 165 substances, i.e. about one third of the substances. Figure 12 summarizes the permeability coefficients for the 108 substances where a permeability coefficient could be obtained (see appendix for details). As can be seen in the figure, there is a trillionfold (1012) range in permeability. Moreover, multiple Kp values are reported for many substances (represented by vertical lines in figure 12) and these withinsubstance deviations are sometimes several orders of magnitude. The wide within-substance range of permeability indicates that experimental design is critical. Thus, the Kp depends on the type of skin (species, location etc.) as well as the exposure conditions (solid, liquid or vapor, neat or diluted, vehicle, exposure duration etc.). One major issue is that of using concentrated versus diluted chemicals. Two concerns already mentioned above is that exposure to neat chemical may affect the skin barrier and may also be unrealistic from the occupational viewpoint. An additional concern is that, at least for some chemicals, the permeability is heavily influenced by dilution with water. Thus, the flux of 2-butoxyethanol reaches its maximum at about 50% dilution and the permeability coefficient increases approximately 100-fold moving from neat to very dilute aqueous solutions (Johanson & Fernström 1988, Korinth, Schaller et al. 2005). Another aspect not covered by our preferred studies approach is that of evaporation. Thus, following exposures of short duration, such as when spills occur at a workplace, some chemical will evaporate back to the atmosphere. This reduces the amount available for dermal penetration. The extent of evaporation depends on the volatility and skin permeability of the chemical, the exposure duration, and the lag time of penetration (Kasting & Miller 2006, N’Dri-Stempfer & Bunge 2005). Theoretical calculations suggest that the fraction lost by evaporation may be significant for volatile chemicals. For example, it has been estimated that following a 1-h exposure to chloroform, 73% of the chemical in the skin evaporates (N’Dri-Stempfer & Bunge 2005). To date, no systematic evaluation of the impact of evaporation has been performed for industrial chemicals. About two thirds of the chemicals with dermal permeability data have a skin notation (table 3 and figure 13). One might expect that skin notations would occur more frequently among chemicals with higher permeability. However, no clear relation between permeability and frequency of skin notation was seen (figure 13).

19

Permeability coefficient (cm/h) 1E-11

1E-10

1E-09

1E-08

1E-07

1E-06

1E-05

1E-04

1E-03

1E-02

1E-01

1E+00

1E+01

1E+02

20

Figure 12. Summary of experimentally determined permeability coefficients (Kp, cm/h) for the investigated chemical. The chemicals are sorted in decreasing order with respect to the preferred value (dots). Ranges of values are given as vertical lines. Note the logarithmic scale of the y axis.

CAS number

7439-97-6 75-21-8 88-06-2 75-15-0 79-11-8 151-67-7 80-62-6 1634-04-4 26675-46-7 106-44-5 95-48-7 67-68-5 79-09-4 108-39-4 10112-91-1 67-56-1 67-66-3 127-19-5 68-12-2 74-90-8 872-50-4 108-10-1 64-17-5 75-01-4 54-11-5 6423-43-4 598-56-1 100-41-4 62-53-3 2807-30-9 420-04-2 107-06-2 108-95-2 75-09-2 71-23-8 102-71-6 111-15-9 124-17-4 10025-73-7 628-96-6 7775-11-3 107-13-1 110-80-5 71-36-3 7487-94-7 50-00-0 59-50-7 107-98-2 120-80-9 7646-79-9 591-78-6 71-43-2 87-86-5 79-01-6 56-23-5 112-34-5 111-76-2 143-33-9 108-38-3 71-55-6 108-46-3 25013-15-4 123-86-4 91-20-3 121-14-2 67-63-0 108-88-3 1303-96-4 1330-20-7 98-01-1 606-20-2 127-18-4 111-90-0 107-15-3 118-96-7 107-21-1 1327-53-3 100-42-5 79-06-1 108-94-1 109-99-9 141-43-5 78-93-3 131-11-3 111-42-2 95-47-6 7778-39-4 55-63-0 67-64-1 25167-83-3 84-66-2 123-31-9 7778-50-9 111-46-6 27323-18-8 25512-42-9 84-74-2 110-54-3 26914-33-0 50-32-8 26601-64-9 142-82-5 107-83-5 117-81-7 13463-67-7 7440-48-4 109-66-0 1327-41-9 111-65-9

It should be pointed out that this grouping solely according to permeability (such as in figure 13) does not take toxic potency into account. The European Centre for Ecotoxicology & Toxicology of Chemicals has suggested a skin notation should be assigned when the amount of chemical absorbed upon exposure of both hands and lower arms (2000 cm2) for one hour is expected to contribute more than 10% to the systemic dose, compared to the amount absorbed via inhalation exposure at the OEL during a full work day (assuming that 10 m3 air is inhaled during an 8-h workday and that 50% is absorbed). This applies only for chemicals for which the OEL is based on systemic toxicity (ECETOC 1993). 60 No skin notation Skin notation

40 30 20

Extremely high

Very high

High

Moderate

Low

No data

No conclusion

0

Very low

10

Extremely low

Number of substances

50

Skin permeability

Figure 13. Number of substances with and without a skin notation in the Swedish OEL list, grouped by experimentally determined skin permeability. This grouping does not take the toxic potency into account.

A comparison between the ECETOC criteria and the Swedish skin notations produces some interesting results (table 3 and figure 14). Thus, two (o-xylene and diethylene glycol) of 12 substances with a dermal/inhalation ratio of less than 0.1 (i.e. should not have a notation according to ECETOC) do have a skin notation in the Swedish list. For o-xylene this is maybe not so controversial, as another study with mixed xylenes in solution yields a ratio above 0.1. On the other hand, 6 out of 14 substances with a ratio between 0.1 and 1 lack a skin notation. Even more remarkable is that 30 out of 82 with a ratio above 1 lack the notation. For the latter chemicals the dermal route contributes to more than 90% of the total dose, according to the ECETOC calculation. For some substances (such as formaldehyde) it may be argued that the systemic dose, and hence the dermal/inhalation ratio, is irrelevant since the OEL is based on a non-systemic effect (such as irritation). Nevertheless these comparisons suggest that a revision of the Swedish skin notations would be appropriate.

21

100 No skin notation Skin notation

Number of substances

80

60

40

20

0 1.0 Dermal/inhalation ratio

No data

Figure 14. Number of substances with and without a skin notation in the Swedish OEL list, categorized by the ratio between dermal and inhalation uptake rate. As inhalation is calculated at the OEL, this ratio does take toxic potency into account. The ECETOC criterion for skin notation (>0.1) is marked by a dotted line.

22

Table 2. Abbreviations and terms as used in tables and appendix. A Ab Abs Ac AoH Ax Ba Br Bw C CAS Chf Der EB Epi Et FH Fi Fk Fl FS FS/TM Full Gas GP H:M Ha Ham Has HD HDP Hep Hex HGP HM HR Hum JP-8 Kp L Loc Log Kow Ma

Area of exposed skin Abdomen Per cent absorbed chemical Acetone Arbete och Hälsa Axilla Back Breast Body weight Concentration of chemical in vehicle Chemical Abstracts Service Registry No. Chloroform Dermis Elbow Epidermis Ethanol Forehead Finger Flank Flow-through diffusion cell Fore skin Fore skin, cultured Full thickness skin Gasoline Guinea pig Hexane:Methylene chloride Hand Hamster Hands Hexadecane Hair Dye Precursors n-Heptane n-Hexane Hairless guinea pig Hairless mouse Hairless rat Human Jet fuel, type JP-8 Permeability coefficient Thickness of exposed skin Body location of the skin Log octanol:water partition coefficient Marmoset

23

Me Mon Mou MP n NaCl n-Bu NC Ne Neat DMF Oct OiW PB PCP PG Ph Ph/NaCl PHD Pit Pol fab Rab Sat Vap Sc SC Sn Solv Sp SpSt St TCP Texp Th Ti Tlag Tobs Tol V Vap VIC WB Yo

Methanol Monkey Mouse Minipig Number of experiments Physiological saline (0.9% NaCl) n-Butanol Nitrocellulose Neck Undiluted chemical Dimethylformamide Octane Oil in water emulsion Phosfate buffer Pentachlorophenol Propyleneglycol Phenol Phenol and saline Permanent Hair Dye Armpit Polyester fabric Rabbit Saturated vapour Scalp Stratum corneum Snake Solvent Examined species Explosive (Sprengstoff in German) Static diffusion cell Tetrachlorophenol Duration of exposure Thigh Tinker soil Time lag for penetration Duration of observation Toluene Applied volume Vapor Vaseline Intensive Care Whole body Yolo soil

a

1993 1993 1993 1993 1993 1984 1993 1996 1993 2004 2004 1990 1993 1978 1987 1989 1987 1987 2000 1984 1984 1984 1984 1978

Year of listing 67-64-1 75-05-8 79-06-1 107-13-1 107-18-6 107-11-9 107-05-1 1327-41-9 62-53-3 7778-39-4 1327-53-3 71-43-2 50-32-8 1303-96-4 78-83-1 71-36-3 78-92-2 75-65-0 123-86-4 78-81-9 109-73-9 13952-84-6 75-64-9 75-15-0

CAS number

Yes Yes Yes Yes Yes Yes Yes No Yes No No Yes No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Yes No Yes Yes No No No Yes Yes Yes Yes Yes Yes Yes No Yes No No Yes No No No No Yes

24

X

Aq. sol.

X

X

Neat liquid

Neat liquid

X X X X X X

>1

Aq. sol. Aq. sol. Aq. sol. Aq. sol. Neat liquid Neat solid Aq. sol.

X

0.1-1

X X

X

1

Neat solid Neat solid Neat liquid Neat solid Aq. sol.

0.1-1 X X

1

Solution Neat liquid Neat liquid

X

0.1-1

X X

X

1

Neat liquid Solution Solution Aq. sol. Neat liquid

0.1-1

X

X X

1

Vapour Neat liquid Neat liquid

X X

0.1-1

X X

X

1

Aq. sol. Aq. sol. Neat liquid Neat liquid Aq. sol.

0.1-1

X

X

X

1

Gas Neat liquid Neat liquid Neat liquid X

0.1-1

X X X

X

6 >6 >6 >6 >6 16

(h)

3.2 2 2.8 0.1

0.4 0.9 2.5 1.3 4.7 5.4 7.5 0.4

(h) (%)

n TExp TObs TLag Abs KP

0.042 0.18 0.6 0.027

0.038 0.31 0.16 0.59 0.68 3.9 0.039

(10 cm/h)

-4

0.0018 0.05 0.00084 1.1-33

0.00011 0.0016 0.00031 0.0016 0.015 0.034 0.39 0.00098

Wester et al. (1993a) Wester et al. (1993a) Lowney et al. (2005) Lowney et al. (2005) Dutkiewicz (1977)

Wester et al. (1993a) Wester et al. (1993a) Bernstam et al. (2002) Bernstam et al. (2002) Bernstam et al. (2002) Bernstam et al. (2002) Bernstam et al. (2002) Turkall et al. (2003)

Flux Reference (µg/cm²/h)

Molecular weight: 141.9 Density: 2 g/cm³ Melting point: 35°C Boiling point: 160°C Vapour pressure: Not available Evaporation rate: Not available Log Kow: -3.14 (estimated)

The permeability of arsenic in monkeys corresponds to "low".

A10

Asessment The Kp of Dutkiewicz (1977) was calculated by Bernstam et al. (2002). Bernstam et al. (2002) used artificial human skin (cultured keratinocytes), therefore the validity of the results is questionable. The same problem applies to the studies by Wester et al. (1993a) that used soil as "vehicle" or used a very small applied volume of 0.01 ml. The preferred study is that of Lowney et al. (2005) who applied an aqueous solution of arsenic acid on the skin of Rhesus monkeys for 8h. The 96-h excretion in urine and faeces was compared to that of a known i.v. dose of arsenic.

Mon Mon Mon Mon Rat

In vivo

Hum Hum Hum Hum Hum Hum Hum Pig

In vitro

Sp

Reported data

Skin notation: No Skin permeability: Low

Substance: Arsenic acid CAS: 7778-39-4 Scientific basis: AoH 1984:44

Appendix A

Br Br Br Br

Fl Fl Fl Fl

Loc Cell

L

A

400 400 400 400

0.1 0.25 0.5 1

(mg/ml)

C

1 1 1 1

>6 >6 >6 >6

(h)

5-6 5-6 5-6 5-6

(h)

-4

KP

0.94 0.96 0.79 1.3

0.0094 0.024 0.04 0.13

Bernstam et al. (2002) Bernstam et al. (2002) Bernstam et al. (2002) Bernstam et al. (2002)

Flux Reference

(h) (%) (10 cm/h) (µg/cm²/h)

n TExp TObs TLag Abs

Molecular weight: 395.7 Density: 3.74 g/cm³ Melting point: 193°C Boiling point: 465°C Vapour pressure: Not available Evaporation rate: Not available Log Kow: -0.13 (estimated)

The reported Kp values correspond to "moderate" permeability.

A11

Asessment The only found study on arsenic trioxide was the one by Bernstam et al. (2002). In the study, artificial human skin (cultured keratinocytes) was used, therefore the validity of the results are questionable.

0.32 0.32 0.32 0.32

H2O H2O H2O H2O

V Vehicle

(µm) (cm²) (ml)

In vivo No data available

Hum Hum Hum Hum

In vitro

Sp

Reported data

Skin notation: No Skin permeability: Moderate

Substance: Arsenic trioxide CAS: 1327-53-3 Scientific basis: AoH 1984:44

Appendix A

Hum Hum Hum Hum Hum Hum Hum Hum Hum Hum Hum Hum Hum Hum Hum Hum Hum Mon MP MP Rat

In vitro

Sp

900 900 Full

Fl Fl

Fl Fl St

Ab

3.1 3.1 2.6

0.2

0.35

(cm²)

(µm)

Epi Epi Epi Epi Epi 40 40 40 Full Full 200-400

A

L

St St St St St St St St

Cell

Ab Ab Ab Ab Ab Ab Ab Ab Br Br Ab/Br

Loc

Reported data

Skin notation: Yes Skin permeability: Moderate

Substance: Benzene CAS: 71-43-2 Scientific basis: AoH 1988:32

1

400 5 µl/cm² 5 µl/cm² 5 µl/cm² 5 µl/cm² 5 µl/cm² 5 µl/cm²

0.035

Inf Inf Inf Inf Inf

(ml)

Vap

H2O Tol Tol Tol Tol H2O H2O

Vap H2O

H2O HD Oct Hex Gas

1.8 44 44 44 44 Neat 0.36 (Saturated) 1.8 (2 µl/ml) Neat Neat 15-50 µg/l 0.44 µg/cm² (0.01%) 4.4 µg/cm² (0.1%) 6.6 µg/cm² (0.15%) 22 µg/cm² (0.5%) 4.4 µg/cm² (0.1%) 22 µg/cm² (0.5%) Neat Neat 0.36 (Saturated) Neat

(mg/ml)

V Vehicle C

6 6 46

13 10 7 210 4 4 4 4 4 4

9

13 14 11

n (h)

TObs (h)

TLag (%)

Abs

KP (10 cm/h)

-4

4 1100 0 9.4 0 37 0 24 0 14 4 21 4 25000 4 1100 0.5 0.25 mg/cm² 5.7 13.5 ~3.7 1.1 8 0.8 600-3300 0.005-0.06 0.12 0.11 0.00046-0.055 0.0042-0.05 0.1 0.0034-0.04 0.08 0.2-2.5 5 0.16-2 3.9 2.5 1.8 18 2.4 18 3800 0.5-2.5 0.67 41-920 µg 2.2

A12

4 4 4 0.5 13.5 8 1-12 1-12 1-12 1-12 1-12 1-12 2.5 18 18 0.5-2.5

4

(h)

TExp

Molecular weight: 78.1 Density: 0.879 g/cm³ Melting point: 5.5°C Boiling point: 80.1°C Vapour pressure: 7.3 kPa (at 20°C) Evaporation rate: Not available Log Kow: 2.13

Appendix A

160 210 140 190

0.000044-0.00053 0.0004-0.0048 0.00055-0.0066 0.0015-0.0176 0.018-0.22 0.072-0.86

0.19 0.044 0.17 0.11 0.061 1800 910 190 500 99

(µg/cm²/h)

Blank et al. (1985) Blank et al. (1985) Blank et al. (1985) Blank et al. (1985) Blank et al. (1985) Blank et al. (1985) Blank et al. (1985) Blank et al. (1985) Loden (1986a) Loden (1986b) Nakai et al. (1997) Wester et al. (2000) Wester et al. (2000) Wester et al. (2000) Wester et al. (2000) Wester et al. (2000) Wester et al. (2000) Franz (1984) Jacobs et al. (1993) Jacobs et al. (1993) Tsuruta (1982)

Flux Reference

Ba WB WB WB Arm Arm Arm WB

Loc

Cell

0.0045

0.05

35-45 13 13 Vap

Vap Vap Vap

Neat 0.0097 (3000ppm) 0.0032 (1000ppm) 0.00064 (200ppm) Neat Neat (3.4 mg/cm²) Neat (68 mg/cm²) 0.13 (40 000ppm)

(mg/ml)

V Vehicle C (ml)

0.8

A

(cm²)

L

(µm)

7 6 6 6 5 3 3 5

n

52 s 2-6 2-6 2-6 2 4 2.5 4

(h)

TExp

4 2-6 2-6 2-6 24 120 168 4

(h)

TObs (h)

TLag

Abs

10 mg 0.17 0.85 0.8

39 µg

(%)

The permeability corresponds to "moderate".

A13

-4 This is in agreement with the in vitro studies using human skin and neat benzene (1, 6 and 21·10 cm/h).

The permeability through human skin in vitro varies tremendously between studies, with Kp values between 1·10-4 cm/h for neat benzene and 3 cm/h for saturated vapour. The only human in vivo study is that of Hanke et al. (2000) (1961, translated in 2000), with a Kp of 3·10-4 to 5·10-4 cm/h.

Asessment Due to lack of information (no e.g. area, volume, duration) in Wester et al. (2000) the duration of the exposure was assumed to be between 1 and 12h due to the small amount (5 µl/cm²) applied, resulting in wide spans for the fluxes and permeabilities.

HM HM HM HM Hum Mon Mon Rat

In vivo

Sp

Appendix A

KP

38 6200 6200 6200 2.8-4.7 0.016 2.6 1500

(10-4 cm/h)

3400 5.9 1.9 0.32 240-400 1.4 230 19

Susten et al. (1985) Tsuruta (1989) Tsuruta (1989) Tsuruta (1989) Hanke et al. (2000) Maibach et al. (1981) Maibach et al. (1981) McDougal et al. (1990)


GP GP GP GP GP HGP HM HM Hum Hum Hum Hum Hum Hum Hum Hum Hum Hum Hum Hum Hum Hum Hum

In vitro

Sp

Ab

Ba Ba Ab Ab FS/TM

Ba Ba Ba Ba

Loc

Reported data

Fl Fl Fl Fl Fl Fl St St St St St St St Fl Fl Fl Fl

Fl Fl Fl Fl

Cell

A

500 200 200 200 Full 200 Full Full 500 500 300 350 350 350 350 350 350 350 500 500 200 1000 Full

(ml)

V Vehicle

0.64 0.01 Ac 0.64 0.01 Ac 0.64 0.01 Ac 0.64 0.01 Ac 5 0.64 0.01 Ac 2 0.01-0.02 Ac 2 0.01-0.02 Ac 0.64 0.01 Ac 0.64 0.01 Ac 0.64 0.01 Ac 1.8 18 mg Soil 1.8 18 mg Soil 1.8 18 mg Soil 1.8 18 mg Soil 1.8 18 mg Soil 1.8 18 mg Soil 1.8 18 mg Soil 1 40 mg Soil 1 0.6 Ac 0.64 0.01 Ac 0.8 5

(µm) (cm²)

L

Skin notation: Yes Skin permeability: Extremely low

Substance: Benzoapyrene CAS: 50-32-8 Scientific basis: Not available

Neat (13 µg/cm²) Neat (8 µg/cm²) Neat (8 µg/cm²) Neat (74 µg/cm²) Neat (10 µg) 0.19 (3µg/cm²) Neat (2.5 µg/cm²) Neat (2.5 µg/cm²) Neat (9.8 µg/cm²) Neat (8.4 µg/cm²) Neat (9.1 µg/cm²) 920 mg soil/kg 140 mg soil/kg 1700 mg soil/kg 110 mg soil/kg 38 mg soil/kg 820 mg soil/kg 630 mg soil/kg 0.014 (10 ppm) Neat (58 µg) 0.19 (3 µg/cm²) 4 µg/cm² Neat (10 µg)

(mg/ml)

C

4

4 5 5 5 4 2-5 10 9 4 4 4 4-5 4-5 4-5 4-5 4-5 4-5 4-5 6 6 2-5

A14

24

24 24 24 24 24 24 16 16 24 24 24 96 96 96 96 96 96 96 24 24 24

(h)

24

48 24 24 24 24 24 16 16 48 48 48 96 96 96 96 96 96 96 24 24 24

(h)

(h)

n TExp TObs TLag

0.01 0.09 0.8 1 2.7

28 37 10 7.2 0.33 4.6 2.9 2 3.3 1.5 0.2

(%)

Abs

Molecular weight: 252.3 Density: 1.351 g/cm³ Melting point: 176.5°C Boiling point: 495°C Vapour pressure: Not available Evaporation rate: Not available Log Kow: 6.13

Appendix A

KP

0.000017

0.0011 0.0009 0.00025 0.0016 0.0000019 0.31 0.000033 0.000023 0.000096 0.000039 0.0000056 110 54 160 27 27 160 110 12 0.000016 0.053

(10 cm/h)

-4

Moody et al. (1995) Ng et al. (1992) Ng et al. (1992) Ng et al. (1992) Kao et al. (1985) Storm et al. (1990) Kao et al. (1988) Kao et al. (1988) Moody et al. (1995) Moody et al. (1995) Moody et al. (1995) Stroo et al. (2005) Stroo et al. (2005) Stroo et al. (2005) Stroo et al. (2005) Stroo et al. (2005) Stroo et al. (2005) Stroo et al. (2005) Wester et al. (1990) Wester et al. (1990) Storm et al. (1990) Hawkins et al. (1986) 0.0023 Kao et al. (1985)

0.15 0.12 0.034 0.22 0.00025 0.0058 0.0045 0.0031 0.013 0.0053 0.00076 13 6.7 20 3.3 3.3 20 13 0.017 0.0022 0.001

(µg/cm²/h)

Flux Reference

Mon Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Pig Rab Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat

Sp

Fl

Fl Fl St St St St St Fl Fl

Ba

Ba

Ba Ba Ba Ba Ba

Ba Ba Ba Ba Ba

Fl Fl Fl Fl Fl Fl Fl Fl Fl Fl Fl Fl Fl Fl

Cell

Ba Ba Ba Ba Ba Ba Ba Ba Ba Ba Ba Ba

Loc

L

A

Full Full Full Full Full Full Full Full Full Full Full Full Full Full Full Full Full Full Full Full 1000 Full 500 200 350 350 320 Full 350 300 300 Full

5 2 2 2 2 2 2 2 2 2 2 2 2 0.64 0.8 5 5 5 5 5 0.8 5 0.64 0.64 1.8 1.8 1.8 1.8 1.8 0.64 0.64 5

(µm) (cm²)

Ac Ac Ac Ac

0.01 Ac 0.01 Ac Oil Soil Solv Solv Solv 0.0096 Ac 0.0096 Ac

0.02 0.02 0.02 0.02

0.01-0.02 0.01-0.02 0.01-0.02 0.01-0.02 0.01-0.02 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01

Ac Ac Ac Ac Ac Ac Ac Ac Ac Ac Ac Ac Ac

V Vehicle (ml)

C (h)

(h)

A15

(h)

n TExp TObs TLag

Neat (10 µg) 4 24 24 Neat (2.5 µg/cm²) 5 16 16 Neat (2.5 µg/cm²) 10 16 16 Neat (2.5 µg/cm²) 10 16 16 Neat (2.5 µg/cm²) 10 16 16 Neat (2.5 µg/cm²) 10 16 16 Neat (10 ng) 17 17 Neat (100 ng) 17 17 Neat (1000 ng) 17 17 Neat (2500 ng) 17 17 Neat (5000 ng) 17 17 Neat (5000 ng) 20 16 16 Neat (10000 ng) 17 17 0.19 (3µg/cm²) 2-5 24 24 4 µg/cm² Neat (5 µg) 4 24 24 Neat (10 µg) 4 24 24 Neat (20 µg) 4 24 24 Neat (30 µg) 4 24 24 Neat (10 µg) 4 24 24 4 µg/cm² Neat (10 µg) 4 24 24 Neat (11 µg/cm²) 4 24 48 0.19 (3µg/cm²) 2-5 24 24 100ppm (90 µg/cm²) 5 96 96 1% (9 mg soil/cm²) 5 96 96 Neat (9.3 - 9.9 µg/cm²) 4 120 120 Neat (9.3 - 9.9 µg/cm²) 4 120 120 Neat (9.3 - 9.9 µg/cm²) 4 120 120 Neat? (2-5 µg/cm²) 3 168 168 Neat? (2-5 µg/cm²) 3 168 168 Neat (10 µg) 4 24 24

(mg/ml)

Appendix A

3.3 6.8 6.8 9.4 9.2 4.4 15 30 25 16 14 11 8 3.1 6 24 17 12 7.2 10 0.6 1.7 51 3.8 38 8.4 2.1 28 50 3.7 56 2

(%)

Abs

KP

0.0014 0.23 0.0048 0.36 0.079 0.0017 0.023 0.04 0.00044-0.0011 0.0067-0.017

0.0017

0.000003-0.0000081 0.00005-0.00013

0.000013

0.01 0.014 0.02 0.018 0.0083

0.0028 0.011 0.011 0.015 0.014 0.0068 0.000044 0.00088 0.0073 0.012 0.021 0.017 0.024 0.0039

Kao et al. (1985) Kao et al. (1988) Kao et al. (1988) Kao et al. (1988) Kao et al. (1988) Kao et al. (1988) Holland et al. (1984) Holland et al. (1984) Holland et al. (1984) Holland et al. (1984) Holland et al. (1984) Holland et al. (1984) Holland et al. (1984) Storm et al. (1990) Hawkins et al. (1986) Kao et al. (1984) Kao et al. (1984) Kao et al. (1984) Kao et al. (1984) Kao et al. (1985) Hawkins et al. (1986) Kao et al. (1985) Moody et al. (1995) Storm et al. (1990) Yang et al. (1989) Yang et al. (1989) Yang et al. (1986) Yang et al. (1986) Yang et al. (1986) Bronaugh et al. (1986) Bronaugh et al. (1986) Kao et al. (1985)


0.00001 0.0017 0.25 0.27 0.058 0.000013 0.00017 0.0003

0.000074 0.0001 0.00015 0.00013 0.000061

0.000021 0.000081 0.000081 0.00011 0.0001 0.00005 0.00000033 0.000006 0.000054 0.00009 0.00016 0.00013 0.00018 0.21

(10-4 cm/h)

Ba Ba Ba Ba Ba Ba Ab Ab Ba Ba Ba Ba Ba Ba Ba Ba

Loc

Cell

L

A

8 8 8 8 4.2 4 12 12 1.8 1.8 1.8 4.2 7 7 1.2 1.25

(µm) (cm²)

0.019 Ac

≤0.015 ≤0.015 ≤0.015 0.05

0.1 0.1 0.1 0.1 0.05 0.05 480 mg

Ac Ac Ac Ac Ac Ac Soil Ac Ac Ac Ac Ac Oil Soil

V Vehicle (ml)

C

Neat (17 µg/cm²) Neat (22 µg/cm²) Neat (32 µg/cm²) Neat (87 µg/cm²) Neat (9.1 µg/cm²) Neat (28 µg) 0.014 (10 ppm) Neat (58 µg) 15 (130 µg/cm²) 15 (130 µg/cm²) 15 (130 µg/cm²) Neat (6.1 µg/cm²) 100ppm (90 µg/cm²) 1% (9 mg soil/cm²) Neat (9.2 µg/cm²) Neat? (2-5 µg/cm²)

(mg/ml) (h)

4 6 6 4 24 24 4 24 48 4 24 168 4 24 336 5 24 168 4 24 144 4 24 144 5-6 24 24 5-6 24 24 5-6 24 24 4 24 336 5 96 96 5 96 96 4 120 120 5 24 192

(h)

(h)

n TExp TObs TLag

4.1 17 23 24 68 73 13 51 41 84 82 69 35 9.2 46 48

(%)

Abs

The Kp of 1·10-7 to 7·10-7 cm/h suggests "extremely low" permeability

A16

The in vivo study by Chu et al. (1996) is preferred since a relatively large amount of benzo[a]pyrene was applied. Further it represents the mid-range of calculated Kp values.

Asessment Nearly all studies only report percent absorbed dose. Fluxes and Kp values were calculated assuming constant flux during the exposure.

GP GP GP GP GP GP Mon Mon Mou Mou Mou Rat Rat Rat Rat Rat

In vivo

Sp

Appendix A

KP

0.0009 0.0011 0.0022 0.0065 0.0019 0.0016 1.6 0.00074 1.4 0.29 0.029 0.0013 0.24 0.064 0.00026 0.0003-0.00074

(10-4 cm/h)

0.12 0.15 0.3 0.87 0.26 0.22 0.0022 0.1 2.1 0.43 0.043 0.17 0.33 0.086 0.035 0.04-0.1

Chu et al. (1996) Chu et al. (1996) Chu et al. (1996) Chu et al. (1996) Moody et al. (1995) Ng et al. (1992) Wester et al. (1990) Wester et al. (1990) Sanders et al. (1984) Sanders et al. (1984) Sanders et al. (1984) Moody et al. (1995) Yang et al. (1989) Yang et al. (1989) Yang et al. (1986) Bronaugh et al. (1986)


Ba

Leg

Loc

Fl

Cell

A

V Vehicle

500

900

1

1.8 H2O

1 H2O

(µm) (cm²) (ml)

L

50 (2 µl/cm²)

50

(mg/ml)

C

8

6

24

(h)

24 168

24

(h)

0.21

0.41

(h) (%)


0.0018

1.7

(10 cm/h)

-4

0.009 Wester et al. (1998b)

A17

The permeability, of the in vitro study (Wester et al. (1998a)), corresponds to "moderate".

8.5 Wester et al. (1998a)

(µg/cm²/h)

Flux Reference

Molecular weight: 381.4 Density: 1.73 g/cm³ Melting point: 75°C Boiling point: 320°C Vapour pressure: Not available Evaporation rate: Not available Log Kow: Not available

Asessment The very low flux and Kp in the in vivo study (Wester et al. (1998b)) is likely due to the small amount applied (2 µl/cm² or 6 µg/cm²).

Hum

In vivo

Hum

In vitro

Sp

Reported data


Substance: Borax CAS: 1303-96-4 Scientific basis: AoH 1983:36

Appendix A

Loc Cell

L

A

V Vehicle

(µm) (cm²) (ml)

(mg/ml)

C (h)

(h)

-4

KP

Flux Reference

Molecular weight: 74.1 Density: 0.802 g/cm³ Melting point: -108°C Boiling point: 107.9°C Vapour pressure: 1.2 kPa (at 20°C) Evaporation rate: 2 Log Kow: 0.76

A18

(h) (%) (10 cm/h) (µg/cm²/h)


Asessment The permeability properties can be assumed to be similar to that of n-butanol.

In vitro No data available In vivo No data available

Sp

Reported data

Skin notation: Yes Skin permeability: No data

Substance: Butanol, isoCAS: 78-83-1 Scientific basis: AoH 1984:44

Appendix A

Dog Hum Hum Hum Hum Hum Hum Hum Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou

In vitro

Sp

Ab/Ba Ab/Ba Ab/Ba Ab/Ba Ab/Ba Ab/Ba Ab/Ba Ab/Ba Ab/Ba Ab/Ba Ab/Ba Ab/Ba Ab Ab Ab Ab

Br Ab Ab Ab Ab

Loc

Reported data

St St St St St Fl Fl Fl St St St St St St St St St St St St St St St St

Cell

A

Full 26.6 2500 26.6 2500 250 250 250 Full Full Full Full Full Full Full Full Full Full Full Full Full Full Full Full

(ml)

V Vehicle

1 2.5 H2O 2.5 H2O 2.5 2.5 1 0.2-0.3 1 0.2-0.3 Tol 1 0.2-0.3 Chf + Me 0.6 1.4 NaCl 0.6 1.4 NaCl 0.6 1.4 NaCl 0.6 1.4 NaCl 0.6 1.4 NaCl 0.6 1.4 NaCl 0.6 1.4 NaCl 0.6 1.4 NaCl 0.6 1.4 NaCl 0.6 1.4 NaCl 0.6 1.4 NaCl 0.6 1.4 NaCl 0.6 0.2 NaCl 0.6 0.2 NaCl 0.6 0.2 NaCl 0.6 0.2 NaCl

(µm) (cm²)

L


Substance: Butanol, nCAS: 71-36-3 Scientific basis: AoH 1984:44

5% 7.4 7.4 Neat Neat Neat 50% 50% 0.0001M 0.0001M 0.0001M 0.0001M 0.0001M 0.0001M 0.0001M 0.0001M 0.0001M 0.0001M 0.0001M 0.0001M

(mg/ml)

C

5 8 3 7 8 3 5 6 4 4 4 4 4 1 4 4 4 4 4 4 3 2 4 5

5

24 21 21 0.3 4.3 7.8 11.3 14.3 26.3 0.3 5.8 9.8 11.3 14.3 26.3 2 2 2 2

24 21 21 0.3 4.3 7.8 11.3 14.3 26.3 0.3 5.8 9.8 13.8 17.8 26.3 2 2 2 2

(h)

5

(h)

A19

(h)

n TExp TObs TLag -4

KP

1.8 (9h) 70 (10h) 22

111 19 220 48 820 330-500

(µg/cm²/h)

Flux Reference

Mills et al. (2003) Scheuplein et al. (1973) Scheuplein et al. (1973) Scheuplein et al. (1973) Scheuplein et al. (1973) Boman et al. (2000) 140-200 5600-8400 Boman et al. (2000) 21-32 840-1300 Boman et al. (2000) 65 Behl et al. (1980) 82 Behl et al. (1980) 120 Behl et al. (1980) 120 Behl et al. (1980) 120 Behl et al. (1980) 120 Behl et al. (1980) 42 Behl et al. (1980) 68 Behl et al. (1980) 73 Behl et al. (1980) 75 Behl et al. (1980) 73 Behl et al. (1980) 79 Behl et al. (1980) 37 Behl et al. (1984) 42 Behl et al. (1984) 87 Behl et al. (1984) 130 Behl et al. (1984)

28 25 300 0.6 10 4.1-6.2

(%) (10 cm/h)

Abs

Molecular weight: 74.1 Density: 0.81 g/cm³ Melting point: -89.5°C Boiling point: 117.6°C Vapour pressure: 0.7 kPa (at 20°C) Evaporation rate: 0.46 Log Kow: 0.88

Appendix A

St St St St St St St St St St St St St St Fl Fl

Cell

L

A

Full Full Full Full Full Full Full Full Full Full Full Full Full Full 900 900

56

0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.79 0.79 0.79 3.1 3.1

(µm) (cm²)

0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2

Vap

NaCl NaCl NaCl NaCl NaCl NaCl NaCl NaCl NaCl NaCl NaCl NaCl NaCl NaCl

V Vehicle (ml)

C

Neat

0.0001M ≤10-4M ≤10-4M ≤10-4M Neat 0.026 (Sat.)

(mg/ml) (h)

2

1

8

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 6 17.5 17.5 6 17.5 17.5

4 5 4 3 2 2 5 4 5 5 5

(h)

(h)

n TExp TObs TLag

29 mg

A20

6.5

41 65 40 87 100 170 240 62 65 51 76 29 44 150 3.7 33000

Similar values (3·10-3 for stratum corneum and 3·10-2 cm/h for full thickness skin) are reported for human skin.

It should be noted that there seems to be a strong vehicle effect of water. Thus, the permeability in mouse skin of n-butanol in physiological saline ranges from 4·10-3 to 2·10-2 cm/h.

(human full thickness skin in vitro) and 7·10-4 cm/h (dog in vivo).

KP

(%) (10-4 cm/h)

Abs

Based on neat solvent, the permeability is considered "moderate" with Kp values of 4·10-4 to 1·10-3 cm/h

Asessment

Dog

Br

Ab Ab Ab Ba Ba Ba Ba Ba Ba Ba Ab Ab Ab Ab

Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou Mou MP MP

In vivo

Loc

Sp

Appendix A

530 DiVincenzo et al. (1979)

300 Jacobs & Phanprasit (1993) 86 Jacobs & Phanprasit (1993)

Behl et al. (1984) Behl et al. (1984) Behl et al. (1984) Behl et al. (1984) Behl et al. (1984) Behl et al. (1984) Behl et al. (1984) Behl et al. (1984) Behl et al. (1984) Behl et al. (1984) Behl et al. (1981) Durrheim et al. (1980) Durrheim et al. (1980) Durrheim et al. (1980)


Loc Cell

L

A

V Vehicle

(µm) (cm²) (ml)

(mg/ml)

C (h)

(h)

-4

KP

Flux Reference

Molecular weight: 74.1 Density: 0.806 g/cm³ Melting point: -115°C Boiling point: 99.5°C Vapour pressure: 1.6 kPa (at 20°C) Evaporation rate: 1.3 Log Kow: 0.61

(h) (%) (10 cm/h) (µg/cm²/h)


A21

According to theoretical calculations by Fiserova-Bergerova et al. (1990) the potential for dermal absorption and resulting toxicity is significant.



Sp

Reported data


Substance: Butanol, sekCAS: 78-92-2 Scientific basis: AoH 1984:44

Appendix A

Loc Cell

L

A

V Vehicle

(µm) (cm²) (ml)

(mg/ml)

C (h)

(h)

-4

KP

Flux Reference

Molecular weight: 74.1 Density: 0.786 g/cm³ Melting point: 25.5°C Boiling point: 82.2°C Vapour pressure: 3.4 kPa (at 20°C) Evaporation rate: 1.1 Log Kow: 0.35

A22

(h) (%) (10 cm/h) (µg/cm²/h)




Sp

Reported data


Substance: Butanol, tertCAS: 75-65-0 Scientific basis: AoH 1984:44

Appendix A

Br

A

V Vehicle

Neat

(mg/ml)

C

3

6

(h)

6

(h)

(h) (%)


Flux Reference

2.2

200 Ursin et al. (1995)

(10 cm/h) (µg/cm²/h)

-4

Molecular weight: 116.2 Density: 0.882 g/cm³ Melting point: -106.2°C Boiling point: 126.1°C Vapour pressure: 1.2 kPa (at 20°C) Evaporation rate: 1 Log Kow: 1.78

The permeability corresponds to "moderate".

A23

Asessment Ursin et al. (1995) stretched the skin when mounting it in the diffusion cell, reaching a final thickness of about one-third of the original thickness. This procedure may give overestimates of the flux and Kp values.

0.64

(µm) (cm²) (ml)

L

St 300-600

Loc Cell


Hum

In vitro

Sp

Reported data


Substance: Butyl acetate, nCAS: 123-86-4 Scientific basis: AoH 1984:44

Appendix A

Loc Cell

L

A

V Vehicle

(µm) (cm²) (ml)

(mg/ml)

C (h)

(h)

-4

KP

Flux Reference

Molecular weight: 73.1 Density: 0.724 g/cm³ Melting point: -85°C Boiling point: 66°C Vapour pressure: 13 kPa (at 18.8°C) Evaporation rate: Not available Log Kow: 0.73

(h) (%) (10 cm/h) (µg/cm²/h)


See also information on n-butylamine.

A24

According to the Swedish consensus document (AoH 1983:36) skin uptake may occur with massive exposure. No further details are given.

Asessment No quantitative experimental data on dermal uptake were found in the literature.


Sp

Reported data


Substance: Butylamine, isoCAS: 78-81-9 Scientific basis: AoH 1983:36

Appendix A

Loc Cell

L

A

V Vehicle

(µm) (cm²) (ml)

(mg/ml)

C (h)

(h)

-4

KP

Flux Reference

Molecular weight: 73.1 Density: 0.741 g/cm³ Melting point: -50°C Boiling point: 77°C Vapour pressure: 11 kPa (at 20°C) Evaporation rate: 7.3 Log Kow: 0.97

(h) (%) (10 cm/h) (µg/cm²/h)


A25

Theoretical calculations by Fiserova-Bergerova et al. (1990) suggest that the potential for dermal absorption and resulting toxicity is significant.

Clayton et al. (1981) (page 3146) refers to a the dermal LD50 of 370 mg/kg bw in guinea pig. This is lower than the oral LD50 in rat (500 mg/kg bw).




Sp

Reported data


Substance: Butylamine, nCAS: 109-73-9 Scientific basis: AoH 1983:36

Appendix A

Loc Cell

L

A

V Vehicle

(µm) (cm²) (ml)

(mg/ml)

C (h)

(h)

-4

KP

Flux Reference

Molecular weight: 73.1 Density: 0.724 g/cm³ Melting point: -85°C Boiling point: 66°C Vapour pressure: 18 kPa (at 20°C) Evaporation rate: Not available Log Kow: 0.74

(h) (%) (10 cm/h) (µg/cm²/h)



A26




Sp

Reported data


Substance: Butylamine, secCAS: 13952-84-6 Scientific basis: AoH 1983:36

Appendix A

Loc Cell

L

A

V Vehicle

(µm) (cm²) (ml)

(mg/ml)

C (h)

(h)

-4

KP

Flux Reference

Molecular weight: 73.1 Density: 0.696 g/cm³ Melting point: -67.5°C Boiling point: 44.4°C Vapour pressure: 48 kPa (at 25°C) Evaporation rate: 1 Log Kow: 0.40

(h) (%) (10 cm/h) (µg/cm²/h)



A27




Sp

Reported data


Substance: Butylamine, tertCAS: 75-64-9 Scientific basis: AoH 1983:36

Appendix A

Loc Cell

Ha

A

V Vehicle

Inf H2O

0.3-1.7

(mg/ml)

C

21

1

(h)

8

(h)

(h)

n TExp TObs TLag -4

KP

Flux Reference

7-37 mg

250-830

20-96 Baranowska (1965)

(%) (10 cm/h) (µg/cm²/h)

Abs

Molecular weight: 76.1 Density: 1.263 g/cm³ Melting point: -110°C Boiling point: 46.2°C Vapour pressure: 35 kPa (at 20°C) Evaporation rate: 23 Log Kow: 1.94

A28

The reported Kp values range between 3·10-2 and 9·10-2 cm/h, suggesting "very high" permeability.

Asessment The only available study is that of Baranowska (1965) (in German) were the subject placed one hand in an aqueous carbon disulfide solution for 1 hour. The uptake of the substance was measured via breath monitoring.

Hum

L

(µm) (cm²) (ml)

In vitro No data available In vivo

Sp

Reported data

Skin notation: Yes Skin permeability: Very high

Substance: Carbon disulfide CAS: 75-15-0 Scientific basis: Not available

Appendix A

Ab

Ab

St

Loc Cell

A

V Vehicle

Full

3.7

0.5

1

(µm) (cm²) (ml)

L

Neat

Neat

(mg/ml)

C (h)

6 0.25

24 2-4 2-4

(h)

(%)

Abs

360 µg

1.4 52-210 µg

(h)

n TExp TObs TLag KP

Flux Reference

3.1

0.13

A29

The preferred study is Tsuruta (1975), were the calculated Kp value suggests "moderate" permeability.

490 Tsuruta (1975)

21 Tsuruta (1977)


-4

Molecular weight: 153.8 Density: 1.594 g/cm³ Melting point: -22.9°C Boiling point: 76.7°C Vapour pressure: 10 kPa (at 20°C) Evaporation rate: 13 Log Kow: 2.83

Asessment The in vitro study of Tsuruta (1977) used physiological saline as the receptor medium, this is unsuitable for highly lipophilic substances. Tsuruta (1975) measured absorption by homogenizing the whole animal. Dermal uptake of carbon tetrachloride has also been shown in humans (Stewart et al. (1964)), however, that study does not contain sufficient data to calculate flux of Kp.

Mou

In vivo

Rat

In vitro

Sp

Reported data


Substance: Carbon tetrachloride CAS: 56-23-5 Scientific basis: Not available

Appendix A

Ba Ba

Ab Ab Ba Ba Ba Ba Ba Ba Ba Ba Ba

Fl Fl Fl Fl Fl Fl Fl Fl Fl Fl Fl

Loc Cell

A

200-320 200-320 200-320 200-320 200-320 200-320 200-320 200-320 200-320 200-320 200-320

0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01

9 0.18 Et 9 0.18 Et

0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64

PHD HDP PHD HDP Et Et Et Et Et Et Et

V Vehicle

(µm) (cm²) (ml)

L

40 40

6 6 6 6 6 6 6 6 6 40 40

(mg/ml)

C

3 3

4 4 9 9

8

3

24 24

0.5 0.5 0.5 0.5 0.5 24 24 24 24 24 24

(h)

24 72

24 24 24 24 24 24 72 24 24 24 72

(h)

45 53

0.4 1.8 0.2 2 6.9 42 49 78 55 81 81

(h) (%)


15 Jung et al. (2003) 18 Jung et al. (2003)

0.98 4.4 0.49 4.9 17 2.1 2.5 3.9 2.8 27 27

A30

It should be noted that either ethanol or hair dye chemicals were used as vehicles, this may have altered the permeability.

3.7 4.4

1.6 7.3 0.81 8.1 28 3.5 4.1 6.6 4.7 6.8 6.9

Jung et al. (2003) Jung et al. (2003) Jung et al. (2003) Jung et al. (2003) Jung et al. (2003) Jung et al. (2003) Jung et al. (2003) Jung et al. (2003) Jung et al. (2003) Jung et al. (2003) Jung et al. (2003)

Flux Reference


-4

Molecular weight: 110.1 Density: 1.3 g/cm³ Melting point: 104°C Boiling point: 245°C Vapour pressure: 660 Pa (at 104°C) Evaporation rate: Not available Log Kow: 0.88

The human in vitro and rat in vivo experiments give Kp values between 2·10-4 and 7·10-4 cm/h, corresponding to "moderate" permeability.

Asessment A number of different experiments yield similar results.

Rat Rat

In vivo

Hum Hum Rat Rat Rat Rat Rat Rat Rat Rat Rat

In vitro

Sp

Reported data


Substance: Catechol CAS: 120-80-9 Scientific basis: AoH 1992:47

Appendix A

Loc Cell

L

A

V Vehicle

(µm) (cm²) (ml)

(mg/ml)

C (h)

(h)

-4

KP

Flux Reference

Molecular weight: 291.98 to 360.86 Density: 1.4 to 1.5 g/cm³ Melting point: Not available Boiling point: 340 to 375°C Vapour pressure: Not available Evaporation rate: Not available Log Kow: 6.34 (estimated)

A31

Data on four congeners (see mono-, di-, tetra- and hexachlorobiphenyl) suggests that the permeability of PCB is "extremely low" to "very low".

Garner et al. (1998) showed that the less chlorinated PCBs penetrate the skin more rapidly. However the metabolism is more rapid for these smaller molecules, resulting in a higher body burden for the higher chlorinated PCBs.

(h) (%) (10 cm/h) (µg/cm²/h)


Asessment No Swedish consensus document or TLV documentation is present.


Sp

Reported data


Substance: Chlorinated biphenyls, poly- (PCB) CAS: 1336-36-3 Scientific basis: Not available

Appendix A

Loc Cell

L

A

V Vehicle

(µm) (cm²) (ml)

(mg/ml)

C (h)

(h)

-4

KP

Flux Reference

Molecular weight: 88.5 Density: Not available Melting point: -130°C Boiling point: 59.4°C Vapour pressure: 23 kPa (at 20°C) Evaporation rate: Not available Log Kow: 2.53 (estimated)

(h) (%) (10 cm/h) (µg/cm²/h)


A32

According to the Swedish criteria group (AoH 1986) and ACGIH (2001) an old study (von Oettingen et al. (1936)) mentions that the substance probably can be absorbed through the skin in amounts large enough to cause acute effects.



Sp

Reported data


Substance: Chloro-1,3-butadiene, 2-; chloroprene CAS: 126-99-8 Scientific basis: AoH 1986:35

Appendix A

Loc Cell

Ba Ba

A

1 (0.15 ml/kg bw) Ac 1 (0.15 ml/kg bw) Ac

(ml)

V Vehicle

Neat (0.4 mg/kg bw) Neat (0.4 mg/kg bw)

(mg/ml)

C

18 18

(h)

48 336 48 336

(h)

(h)

n TExp TObs TLag

85 (24h) 66 (24h)

(%)

Abs

The two studies show consistent results, with the calculated Kp values ranging between 2·10-6 and 3·10-6 cm/h, suggesting "very low" permeability.

A33

-4

KP

Flux Reference

0.026 0.02

3.5 Garner & Matthews (1998) 2.8 Garner et al. (2006)


Molecular weight: Not available Density: 1.4 g/cm³ Melting point: 149°C Boiling point: Not available Vapour pressure: Not available Evaporation rate: Not available Log Kow: 5.59 (estimated)

Asessment The two studies by Garner were conducted in similar fashion except for method of measuring absorbed amount. This was done in carcass (Garner & Matthews (1998)) and in urine and faeces (Garner et al. (2006)), respectively.

Rat Rat

L

(µm) (cm²)


Sp

Reported data

Skin notation: Yes Skin permeability: Very low

Substance: Chlorobiphenyl, di- (DCB) CAS: 25512-42-9 Scientific basis: Not available

Appendix A

Loc Cell

Ba Ba

A


(ml)

V Vehicle

Neat (0.4 mg/kg bw) Neat (0.4 mg/kg bw)

(mg/ml)

C

18 18

(h)

48 336 48 336

(h)

(h)

n TExp TObs TLag -4

The two studies show consistent results, with the calculated Kp values ranging between 2·10-7 and 4·10-7 cm/h, suggesting "extremely low" permeability.

A34

KP

Flux Reference

9 (24h) 19 (24h)

0.002 0.0044


(%) (10 cm/h) (µg/cm²/h)

Abs

Molecular weight: 360.9 Density: 1.8 g/cm³ Melting point: 201 to 202°C Boiling point: Not available Vapour pressure: Not available Evaporation rate: Not available Log Kow: 7.75


Rat Rat

L

(µm) (cm²)


Sp

Reported data


Substance: Chlorobiphenyl, hexa- (HCB) CAS: 26601-64-9 Scientific basis: Not available

Appendix A

Loc Cell

Ba Ba

A


(ml)

V Vehicle (h)

48 336 48 336

(h)

(h)

n TExp TObs TLag

Neat (0.4 mg/kg bw) 18 Neat (0.4 mg/kg bw) 18

(mg/ml)

C

98 (24h) 69 (24h)

(%)

Abs

The two studies show consistent results, with the calculated Kp values ranging between 3·10-6 and 4·10-6 cm/h, suggesting "very low" permeability.

A35

-4

KP

Flux Reference

0.037 0.026



Molecular weight: Not available Density: 1.1 g/cm³ Melting point: 10°C Boiling point: 365°C Vapour pressure: Not available Evaporation rate: Not available Log Kow: 4.58


Rat Rat

L

(µm) (cm²)


Sp

Reported data

Skin notation: Yes Skin permeability: Very low

Substance: Chlorobiphenyl, mono- (MCB) CAS: 27323-18-8 Scientific basis: Not available

Appendix A

Loc Cell

Ba Ba

A


(ml)

V Vehicle (h)

48 336 48 336

(h)

(h)

n TExp TObs TLag

Neat (0.4 mg/kg bw) 18 Neat (0.4 mg/kg bw) 18

(mg/ml)

C

37 (24h) 8 (24h)

(%)

Abs

The two studies show rather consistent results, with the calculated Kp values ranging between 2·10-7 and 1·10-6 cm/h, suggesting "extremely low" permeability.

A36

-4

KP

Flux Reference

0.0096 0.0019



Molecular weight: 292.0 Density: 1.6 g/cm³ Melting point: ~170°C Boiling point: ~360°C Vapour pressure: Not available Evaporation rate: Not available Log Kow: 6.09


Rat Rat

L

(µm) (cm²)


Sp

Reported data


Substance: Chlorobiphenyl, tetra- (TCB) CAS: 26914-33-0 Scientific basis: Not available

Appendix A

Ab

St

Loc Cell

A

V Vehicle

Epi

8 8 8 8

2.5

0.2 0.2 0.2 0.2

H2O + Gel H2O oil/ac PG

Inf H2O

(µm) (cm²) (ml)

L

5% (10 mg) 0.4% (Saturated. 0.8 mg) 5% (10 mg) 5% (10 mg)

4

(mg/ml)

C

19 20 20 20

2

24 24 24 24

8

(h)

96 96 96 96

-4

KP

75 54 34 35

A37

The reported Kp value for saturated chlorophenol in water of 6·10 -4 cm/h, suggests "moderate" permeability.

The preferred in vivo experiment is by Andersen et al. (1985) using water as vehicle.

Flux Reference

8.7 5.8 4 4

550

39 2.3 18 18

Andersen et al. (1985) Andersen et al. (1985) Andersen et al. (1985) Andersen et al. (1985)

220 Roberts et al. (1977)

(h) (%) (10 cm/h) (µg/cm²/h)

8 0.3

(h)


Molecular weight: 142.6 Density: 0.9 g/cm³ Melting point: 67°C Boiling point: 235°C Vapour pressure: 13 Pa (at 20°C) Evaporation rate: Not available Log Kow: 3.10

Asessment In the experiments by Roberts et al. (1977), epidermal sheets were separated by exposing skin to ammonia vapour for 30 min. Ammonia is well known to cause severe skin damage Amshel et al. (2000). The alkaline nature of ammonia quickly saponifies the epidermal fats, thus destroying the protective structure of the epidermis. Therefore, the method used by Roberts et al. (1977) is likely to result in severe overestimates of the flux and Kp value of undamaged skin.

GP GP GP GP

In vivo

Hum

In vitro

Sp

Reported data


Substance: Chlorocresol; 4-chloro-3-methylphenol CAS: 59-50-7 Scientific basis: Not available

Appendix A

Loc Cell

L

A

V Vehicle

(µm) (cm²) (ml)

(mg/ml)

C (h)

(h)

-4

KP

Flux Reference

Molecular weight: 80.5 Density: 1.201 g/cm³ Melting point: -89°C Boiling point: 130°C Vapour pressure: 0.66 kPa (at 20°C) Evaporation rate: Not available Log Kow: 0.03

(h) (%) (10 cm/h) (µg/cm²/h)


A38

No documentation by the Swedish consensus group or ACGIH was found for this substance. The acute dermal toxicity is extremely high. Thus, application of 2 ml on the skin caused 80% mortality in 1 hour and a dose of 1 ml caused 80-100% mortality within 1 week in guinea pigs (Wahlberg et al. (1979)).



Sp

Reported data


Substance: Chloroethanol, 2CAS: 107-07-3 Scientific basis: Not available

Appendix A

WB WB WB Ba Ba Ba Arm Arm WB WB Ab

Ab Ab Ab Ab

Loc

Fl Fl Fl Fl

Cell

L A

V Vehicle

300 300 200-400 200-400

Inf Inf Inf 0.35 0.35 0.35 0.05 0.05 Inf Inf 2.9 0.5

~300 460 510 5.46 5.46 5.46 3.1 3.1 H2O Et H2O H2O

H2O H2O H2O

0.64 1 H2O 0.64 0.05 H2O 0.2 Inf H2O 0.2 Inf H2O

(µm) (cm²) (ml)

C

19-52 ppb 0.44 0.44 Neat Neat Neat 1 (50 µg) 5 (250 µg) 40 µg/l 60-150 µg/l (40-97 ppb) Neat

400 µg/l (0.62 µg/cm²) 0.9 (70 µg/cm²) 140-290 µg/l 140-290 µg/l

(mg/ml)

4 4 6 6

(h)

TExp

4 4 6 6

(h)

(h)

TObs TLag

6 1.2 2-4w 3 0.5 0.5 4 0.5 6 3 1 min 6 3 3 min 6 3 8 min 6 3 8 72 4 8 72 6 0.5 2.5 9 0.5 ~1 10 0.25

19 19

n

12-44 µg 1700 µg

20 mg 10 mg 2.8 mg 3.5 mg 13 mg 8.2 1.7

4.1 (2h) 6.5 (2h)

(%)

Abs

Molecular weight: 119.4 Density: 1.498 g/cm³ Melting point: -63.7°C Boiling point: 61.7°C Vapour pressure: 18 kPa (at 20°C) Evaporation rate: 0.09 Log Kow: 1.97

A39

Asessment The experiment using ethanol as vehicle is disregarded as skin permeability may be affected. The in vitro Kp value of Dick et al. (1995) is calculated during the first 2h of exposure, due to possible depletion. The in vivo study of Dick et al. (1995) was performed unoccluded, hence the low absorption/Kp values. Tsuruta (1975) measured absorption by homogenizing the whole animal. This method may severely underestimate skin permeability. The preferred experiment is that of Islam et al. (1999), using neat chloroform and hairless rat in vivo and the longest exposure duration (8 min). The Kp value of 1·10-2 suggest "very high" permeability.

HGP HR HR HR HR HR Hum Hum Hum Hum Mou

In vivo

Hum Hum Hum Hum

In vitro

Sp

Reported data

Skin notation: No Skin permeability: Very high

Substance: Chloroform; trichloromethane CAS: 67-66-3 Scientific basis: Not available

Appendix A

KP

1300 2900 900 210 85 120 1.7 0.34 150 600 16

320 26 1400 1700

(10-4 cm/h)

Flux Reference

Bogen et al. (1992) Islam et al. (1995) Islam et al. (1996) Islam et al. (1999) Islam et al. (1999) Islam et al. (1999) Dick et al. (1995) Dick et al. (1995) Xu et al. (2005) 0.0036-0.009 Corley et al. (2000) 2400 Tsuruta (1975) 130 40 31000 13000 18000 0.17 0.17 0.0006

0.013 Dick et al. (1995) 2.3 Dick et al. (1995) Nakai et al. (1999) Nakai et al. (1999)

(µg/cm²/h)

WB

Ab

Loc

St

Cell

(cm²)

(µm)

(ml)

V Vehicle

~13000

Inf H2O

Full 0.7/1.8 556 µl/cm² H2O

A

L (h)

(h)

0.022

4

3

96

(h) (%)


0.5% (0.034 M) 3 190 190

(mg/ml)

C

A40

It should be noted that the reported Kp value of sodium chromate is two orders of magnitude higher.

The reported Kp value suggests "extremely low" permeability.

KP

Flux Reference

0.068

0.00014

0.00015 Corbett et al. (1997)

0.00019 Gammelgaard et al. (1992)


-4

Molecular weight: 294.2 Density: 2.676 g/cm³ Melting point: 398°C Boiling point: 500°C Vapour pressure: Not available Evaporation rate: Not available Log Kow: -3.59 (estimated)

Asessment Only one study was found on potassium dichromate. In Gammelgaard et al. (1992), human abdominal skin was exposed to aqueous solution.

Hum

In vivo

Hum

In vitro

Sp

Reported data

Skin notation: No Skin permeability: Very low

Substance: Chromate, potassium diCAS: 7778-50-9 Scientific basis: AoH 2000:22

Appendix A

Ba Ba Ba Ba Ba Arm Arm Arm

Ba Ba Ba Ba Ba Ab Ab Ab Ab Ab

Loc

Fl

Fl

Cell

L

A

Full Full Full Full Full Full Full Full Full Full

3.1

3.1 3.1 3.1 3.1 3.1 3.1 3.1 3.1 3.1 3.1

1 1 1 1

1 1 1 1

1 1 1 1

H2O H2O H2O H2O H2O H2O H2O H2O H2O

H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O

V Vehicle

(µm) (cm²) (ml)

C

2.8-65 (0.017-0.398 M) 5.5 (0.034 M) 2.8 (0.017 M) 13 (0.080 M) 42 (0.261 M) 65 (0.398 M) 1.6 (0.01M) 16 (0.1M) 32 (0.2M)

5.5 (0.034 M) 2.8 (0.017 M) 13 (0.080 M) 39 (0.239 M) 65 (0.398 M) 5.5 (0.034 M) 2.8 (0.017 M) 13 (0.080 M) 39 (0.239 M) 65 (0.398 M)

(mg/ml)

20 10 5 5 5 5 9 9 9

10 5 5 5 5 10 5 5 5 5 5 48 24 24 24 24 1 1 1

48 24 24 24 24 48 24 24 24 24

(h)

5 48 24 24 24 24 1 1 1

48 24 24 24 24 48 24 24 24 24

(h)

(h) (%)


A41

17-18 12 18 13 26 18 6.9 4.1 3.1

11 19 15 14 12 3.3 8.7 13 14 15 4.9-120 6.8 4.9 17 110 120 1.1 6.5 10

6.2 5.2 20 54 75 1.8 2.4 17 54 97

Wahlberg et al. (1965) Wahlberg (1965) Wahlberg et al. (1963) Wahlberg et al. (1963) Wahlberg et al. (1963) Wahlberg et al. (1963) Baranowska-Dutkiewicz (1981) Baranowska-Dutkiewicz (1981) Baranowska-Dutkiewicz (1981)

Wahlberg (1965) Wahlberg (1970) Wahlberg (1970) Wahlberg (1970) Wahlberg (1970) Wahlberg (1965) Wahlberg (1970) Wahlberg (1970) Wahlberg (1970) Wahlberg (1970)

Flux Reference

(10-4 cm/h) (µg/cm²/h)

KP

Molecular weight: 162.0 Density: 2.7 g/cm³ Melting point: 792°C Boiling point: Not available Vapour pressure: Not available Evaporation rate: Not available Log Kow: Not available

Asessment Human and guinea pig data suggest "high" permeability of sodium dichromate, with Kp values between 3·10-4 and 3·10-3 cm/h. It should be noted that the reported Kp value for potassium dichromate is two orders of magnitude lower.

GP GP GP GP GP GP Hum Hum Hum

In vivo

GP GP GP GP GP Hum Hum Hum Hum Hum

In vitro

Sp

Reported data

Skin notation: No Skin permeability: High

Substance: Chromate, sodium diCAS: 7775-11-3 Scientific basis: AoH 2000:22

Appendix A

Ba Ba Ba Ba Ba Ba Ba Ba Ba Ab Ab Ab Ab

Fl Fl Fl Fl Fl

Loc Cell

L

A

Full Full Full Full Full Full Full Full Full Full Full Full Full 1 1 1 1

1 1 1 1

2.7 (0.017 M) 13 (0.080 M) 38 (0.239 M) 63 (0.398 M) 2.7 (0.017 M) 13 (0.080 M) 20 (0.126 M) 38 (0.239 M) 41 (0.261 M) 2.7 (0.017 M) 13 (0.080 M) 38 (0.239 M) 63 (0.398 M)

(mg/ml)

C

5 5 5 5 10 10 10 10 10 5 5 5 5

24 24 24 24 48 48 48 48 48 24 24 24 24

(h)

24 24 24 24 48 48 48 48 48 24 24 24 24

(h)

-4

KP

20 20 21 15 15 10 12 13 13 15 13 11 12

5.5 26 81 91 4 13 24 50 52 4 16 40 75

A42

Wahlberg (1970) Wahlberg (1970) Wahlberg (1970) Wahlberg (1970) Wahlberg (1965) Wahlberg (1965) Wahlberg (1965) Wahlberg (1965) Wahlberg (1965) Wahlberg (1970) Wahlberg (1970) Wahlberg (1970) Wahlberg (1970)

Flux Reference

(h) (%) (10 cm/h) (µg/cm²/h)


Molecular weight: 158.4 Density: 2.76 g/cm³ Melting point: 1152°C Boiling point: Not available Vapour pressure: Not available Evaporation rate: Not available Log Kow: 1.16 (estimated)

Asessment The calculated Kp values (two studies only) on chromate chloride are consistent. The preferred experiments are those on human skin, with calculated Kp values corresponding to "high" permeability.

3.1 3.1 3.1 3.1 3.1 3.1 3.1 3.1 3.1 3.1 3.1 3.1 3.1

H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O

V Vehicle

(µm) (cm²) (ml)


GP GP GP GP GP GP GP GP GP Hum Hum Hum Hum

In vitro

Sp

Reported data


Substance: Chromic chloride CAS: 10025-73-7 Scientific basis: AoH 2000:22

Appendix A

Ha

Ab

St

Loc Cell

Full

(µm)

L

V Vehicle

390

Inf Powder

1 NaCl

(cm²) (ml)

A

5-15% (0.05-0.25 mg/m³)

50

(mg/ml)

C

4

7

1.5

24

(h)

(h) (%)

72

24 1.55

(h)


0.0025

0.0003-0.0009

The preferred study is that of Scansetti et al. (1994). The Kp value corresponds to "extremely low" permeability.

A43

KP

Flux Reference

0.04 Scansetti et al. (1994)

0.012 Larese Filon et al. (2004)


-4

Molecular weight: 58.9 Density: 8.92 g/cm³ Melting point: 1495°C Boiling point: 2870°C Vapour pressure: Not available Evaporation rate: Not available Log Kow: 0.23 (estimated)

Asessment The two found studies report fairly consistent Kp values, ranging between 3·10-7 and 3·10-8 cm/h.

Hum

In vivo

Hum

In vitro

Sp

Reported data

Skin notation: No Skin permeability: Extremely low

Substance: Cobalt CAS: 7440-48-4 Scientific basis: AoH 2004:16

Appendix A

Ba Ba

Ba Ab/Br

Loc

Fl Fl

Cell

A

Full Full

3.1

3.1 3.1

5.0 (0.085M) 5.0 (0.085M)

(mg/ml)

C

H2O 5.0 (0.085M) 0.1 NaCl/Et 20

H2O H2O

V Vehicle

(µm) (cm²) (ml)

L

10 4

10 10

48 48

48 48

(h)

48 48

48 48

(h)

-4

KP

Flux Reference

60

13-22

12 4.4

A44

The three studies of Wahlberg (1965) show consistent results. The preferred experiment is that with human skin. The Kp value corresponds to "moderate" permeability.

6.6-11 Wahlberg (1965) Lacy et al. (1996)

6.2 Wahlberg (1965) 2.2 Wahlberg (1965)

(h) (%) (10 cm/h) (µg/cm²/h)


Molecular weight: 129.8 Density: 3.356 g/cm³ Melting point: 735°C Boiling point: 1049°C Vapour pressure: 5.3 kPa (at 770°C) Evaporation rate: Not available Log Kow: 0.85 (estimated)

Asessment The study by Lacy et al. (1996) gives no area of exposure, therefore no Kp or flux value can be calculated. The high absorption shows that cobalt dichloride readily penetrates the skin.

GP Ham

In vivo

GP Hum

In vitro

Sp

Reported data


Substance: Cobalt dichloride CAS: 7646-79-9 Scientific basis: AoH 2004:16

Appendix A

Ab Ba

St St

Loc Cell

L

A

V Vehicle

Epi Full

Inf H2O PBS

4 1-3

(mg/ml)

C

2 4

8 6

(h)

(h) (%)

8 0.25 6

(h)


Flux Reference

150 99

60 Roberts et al. (1977) 9.9-30 Itoh et al. (1990)


-4

Molecular weight: 108.1 Density: 1.034 g/cm³ Melting point: 11.5°C Boiling point: 202.2°C Vapour pressure: 13 Pa (at 20°C) Evaporation rate: Not available Log Kow: 1.96

A45

It should be noted that in the experiments by Roberts et al. (1977), epidermal sheets were separated by exposing skin to ammonia vapour for 30 min. Ammonia is well known to cause severe skin damage Amshel et al. (2000). The alkaline nature of ammonia quickly saponifies the epidermal fats, thus destroying the protective structure of the epidermis. Therefore, the method used by Roberts et al. (1977) is likely to result in severe overestimates of the flux and Kp value of undamaged skin.

The preferred study is that of Roberts et al. (1977), where the reported Kp value of 2·10-2 cm/h suggest "high" permeability.

Asessment In the study by Itoh et al. (1990), snake skin was used. As this is very different from human skin, this data is disregarded.

2.5 1.8

(µm) (cm²) (ml)


Hum Sn

In vitro

Sp

Reported data


Substance: Cresol, mCAS: 108-39-4 Scientific basis: AoH 1998:25

Appendix A

Ab

St

Loc Cell

L

A

V Vehicle

Epi

Inf H2O

4

(mg/ml)

C

2

8

(h)

(h) (%)

8 0.25

(h)


Flux Reference

160



-4

Molecular weight: 108.1 Density: 1.048 g/cm³ Melting point: 30.9°C Boiling point: 191°C Vapour pressure: 33 Pa (at 25°C) Evaporation rate: Not available Log Kow: 1.95

A46


Asessment Only one study was found on o-cresol. The study by Roberts et al. (1977) reported a Kp value of 2·10-2 cm/h, suggesting "high" permeability.

2.5

(µm) (cm²) (ml)


Hum

In vitro

Sp

Reported data


Substance: Cresol, oCAS: 95-48-7 Scientific basis: AoH 1998:25

Appendix A

Ab

St

Loc Cell

L

A

V Vehicle

Epi

Inf H2O

4

(mg/ml)

C

2

8

(h)

(h) (%)

8 0.27

(h)


Flux Reference

180



-4

Molecular weight: 108.1 Density: 1.034 g/cm³ Melting point: 32 to 34°C Boiling point: 201.8°C Vapour pressure: 15 Pa (at 25°C) Evaporation rate: Not available Log Kow: 1.94

A47


Asessment Only one study was found on o-cresol. The study by Roberts et al. (1977) reported a Kp value of 2·10-2 cm/h, suggesting "high" permeability.

2.5

(µm) (cm²) (ml)


Hum

In vitro

Sp

Reported data


Substance: Cresol, pCAS: 106-44-5 Scientific basis: AoH 1998:25

Appendix A

Loc

Cell

Arm

A

V Vehicle

16

1 H2O

1% (10mg)

(mg/ml)

C

6

6

(h)

48

(h)

(h)

n TExp TObs TLag

Asessment The only study found on cyanamide was that by Mertschenk et al. (1991) where the calculated Kp value corresponds to "high" permeability.

Hum

L

(µm) (cm²) (ml)


Sp

Reported data


Substance: Cyanamide, hydrogen CAS: 420-04-2 Scientific basis: AoH 1999:25

A48

7.7 (2.3 mg)

(%)

Abs

KP

Flux Reference

24

24 Mertschenk et al. (1991)


-4

Molecular weight: 42.0 Density: 1.06 g/cm³ Melting point: 42°C Boiling point: 260°C Vapour pressure: Not available Evaporation rate: Not available Log Kow: -0.82

Appendix A

Loc Cell

Ha

A

V Vehicle

Inf

Neat

(mg/ml)

C

3

0.5

(h)

72

(h)

(h) (%)


Flux Reference

0.59

56 Mraz et al. (1994)


-4

Molecular weight: 98.1 Density: 0.947 g/cm³ Melting point: -47°C Boiling point: 155.6°C Vapour pressure: 0.69 kPa (at 25°C) Evaporation rate: 0.23 Log Kow: 0.81

The calculated Kp value of 6·10-5 cm/h, suggests "low" permeability.

A49

Asessment A single human in vivo study was found (Mraz et al. (1994)). The flux was obtained by analyzing the urinary excretion of 1,4-cyclohexanediol after both dermal and inhalational exposure.

Hum

L

(µm) (cm²) (ml)


Sp

Reported data

Skin notation: Yes Skin permeability: Low

Substance: Cyclohexanone CAS: 108-94-1 Scientific basis: AoH 1999:25

Appendix A

GP GP GP GP GP Hum Rat Rat

In vivo

GP GP GP GP Hum Hum Pig Rat Rat Rat Rat Rat Rat

In vitro

Sp

Ba Ba Ba Ba Ba

Ba Ba Ba Ba Ba Arm Ba Ba

St Fl Fl Fl Fl St

Ab

Cell

Fl Fl Fl Fl St St

Ba Ba Ba Ba

Loc

Reported data V Vehicle

(cm²) (ml)

A

8 0.1 Ac 8 0.1 Ac 8 0.1 Ac 8 0.1 Ac 4 0.05 Ac 10 0.05 Et 15 Film 1.3

200 0.64 0.01 Ac 200 0.64 0.01 Ac 200 0.64 0.01 Ac 200 0.64 0.01 Ac Epi 0.64/1.0 Epi 1.8 0.5 Full 10 0.05 Et Full 0.64/1.0 Epi 0.64 0.05 Ac Derm 0.64 0.05 Ac Epi 0.64 0.05 Ac Derm 0.64 0.05 Ac Epi 1.8 0.5

(µm)

L

Skin notation: No Skin permeability: Extremely low

Substance: Di-(2-ethylhexyl)phthalate (DEHP) CAS: 117-81-7 Scientific basis: AoH 1983:36

9.5 8.6 35 42 4.2 3.7 400mg 5-8 mg/cm²

0.89 0.89 3.8 7.8 Neat Neat 3.7 Neat 1.6 1.6 1.6 1.6 Neat

(mg/ml)

C

24 24 24 24 32 72 8 32 72 72 72 72 53

4 24 4 24 4 24 4 24 5 24 6 24 4 24 3 168

5 5 5 5 4 9 5 11 8 11 9 9 9

(h)

n TExp

24 48 168 336 168 168 24 168

24 24 24 24 32 72 8 32 72 72 72 72 53

(h)

A50

13 19 19 9.7 53 1.8 0.1 7

0.1 1-2 2.58 51 1.17 5.6 2.47 1.2 0.91 1.7 3.9

1-2 3.1

6.1 5 2.4 2.5

(h) (%)

TObs TLag Abs

KP

0.67 0.97 0.98 0.51 2.8 0.038 0.0025 0.034

0.4 0.33 0.16 0.16 0.0011 0.057 0.0088 0.0043 9.5 0.98 0.13 0.48 0.23

(10 cm/h)

-4

Molecular weight: 390.6 Density: 0.973 g/cm³ Melting point: -50°C Boiling point: 286.9°C Vapour pressure: 1 Pa (at 20°C) Evaporation rate:

Basis for skin notation. Part 1.

Basis for skin notation. Part 1.

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